Liquid formulation compositions, medicament delivery devices, and methods of preparation and use thereof

ABSTRACT

The invention provides liquid formulation compositions and medicament delivery devices, and methods for preparing and using the same. For example, the liquid formulation composition is an emulsion including a solvent and liquid particles, which includes surfactants and are dispersed in the solvent. The volume average particle size of the liquid particles is less than about 100 μm; the surface tension of the liquid formulation composition is less than about 60 mN/m; and the absolute value of zeta potential is greater than about 15 mV. The containment vessel may be a sprayer or a dropping device. The invention also provides methods for preparation of the liquid formulation compositions and medicament delivery devices as well as methods for using the same in treatment of various diseases and condition, for example, otitis media, otitis externa, rhinitis, sinusitis, lower respiratory tract inflammation, xerostomia (dry mouth), xerophthalmia (dry eyes) and xeromycteria (dry nose).

PRIORITY CLAIMS AND RELATED APPLICATIONS

This application claims the benefit of Chinese Application Nos.CN201410390825.9, CN201410391082.7, CN201410391083.1 andCN201410391084.6, all filed Aug. 8, 2014, the entire content of each ofwhich is incorporated herein by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

The invention relates to liquid formulation compositions and medicamentdelivery devices, and methods for preparing and using the same.

BACKGROUND OF THE INVENTION

Otitis media, otitis externa, rhinitis and sinusitis are the mostcommonly occurred otorhinolaryngologic diseases.

Otitis media is an inflammatory lesion involving all or part of thestructure of middle ear (including Eustachian tube, tympanic cavity,tympanic sinus and mastoid air cells) and are more common in children,but can occur at any age. There are two major types of otitis media,namely acute otitis media and otitis media with effusion. The former isusually symptomatic, especially ear pain, whereas the latter is mostcommonly without acute symptoms. Chronic suppurative otitis media,incorrectly called “chronic otitis media,” is less common and is acomplication of acute otitis media, and is associated with perforationof the ear drum, with or without drainage. All these conditions are mostfrequently associated with hearing loss. Barotitis media, or airplaneear, diver's ear, is caused by pressure change during aircraft takeoffand landing, water pressure increase during diving and the like. Duringa sudden increase in ambient pressure, gas must move from thenasopharynx into the middle ear to maintain equal pressure on both sidesof the tympanic membrane. If the Eustachian tube is not functioningproperly, the pressure in the middle ear is lower than the ambientpressure. The relative negative pressure in the middle ear results inretraction of the tympanic membrane and pain.

Otitis externa is an inflammation due to infection of external earcanal, and is often caused by injuries made during ear picking, earscratching and/or contaminated water entering the external ear canal.Otitis externa can induce swelling of local skin of the external earcanal, accompanied by pain or tenderness, external ear itching andexternal ear secretion increase. There are two types of otitis externa,namely diffuse otitis externa and partial otitis externa. Because otitisexterna commonly affects swimmers, it is sometimes known as swimmer'sear.

Rhinitis is the common name for symptoms caused by irritation orinflammation of nasal mucosa and includes allergic rhinitis, sinusitis,acute rhinitis and the like. The symptoms of rhinitis include nasalobstruction, runny nose, itching and sneezing, and severe rhinitis cancause headache, dizziness and decreased sense of smell. The causes andthe symptoms of the above diseases are briefly described as follows:

Otitis media is generally caused by periodic open function disorders ofthe Eustachian tube. Eustachian tube (ET) is the only channel for airdraining of the middle ear. The main function of Eustachian tube is tolead air in nasopharynx to the tympanic cavity to keep the pressurebalanced on the two sides of tympanic membrane and further ensure normalvibration of the tympanic membrane. Mucosa of the Eustachian tube isconnected with the mucosa of the tympanic cavity in nasopharynx, whichis comprised with pseudostratified ciliated columnar epithelial cellsand considerable number of secretory cells. Thin liquid (mucus) secretedby these cells can not only prevent the Eustachian tube from beingopened completely, but also enable the Eustachian tube to be openedoccasionally at appropriate opportunities, such as opening mouth,swallowing, yawning or chewing, thereby regulating the pressure in thetympanic cavity and keeping the balance of the pressures inside andoutside the tympanic cavity. When the Eustachian tube has a dysfunction,the pressure imbalance on the two sides of the tympanum occurs whileeffusion in a cavity canal cannot be discharged timely, which can bringextreme agony to a patient. Earache is an early clinical symptom, anddeafness, tinnitus, dizziness and other symptoms are easy to be ignoredwhen being masked by earache. Systemic symptoms are different due topatient resistance and virulence of infecting bacteria and oftencomprise aversion to cold, fever, body discomfort, loss of appetite andthe like. The characteristics of headache are represented as follows:the severe earache firstly occurs in the initial stage of the diseaseand then radiates to temporal occipitoparietal part on the same side asthe affected ear, thereby causing unbearable hemi-headache. If theEustachian tube is blocked, the pressure in the tympanic cavity may bereduced, and the external pressure is relatively increased, therebyenabling the tympanic membrane to sink inwards and affecting hearing.

Studies report that in samples of patients with secretory otitis media,the content of phospholipid representing a surfactant is discerniblyreduced in comparison with that of a normal (healthy) control group. Thedifference has statistical significance (p<0.01), which confirms thatthe reduction of the surfactant in the patients with secretory otitismedia is mainly shown in the nasopharynx, the middle ear and part of theEustachian tube. The leads to an increase in the open pressure of theEustachian tube and enables the compliance to be possible, causing theeffusion in middle ear cavity and the retention of the effusion,resulting in secretory otitis media. (Qiu, et al, 1999 Journal of WestChina University of Medical Sciences. 30(3): 310-311.) The reduction ofthe content of the phospholipid is also reported in the patients withthe rhinitis. (Sayed, et al. 2000 J Laryngol Otol. April; 114(4): 254-9;Schlosser, 2006 Ann Otol Rhinol Laryngol Suppl. September 196: 40-4.)

There are many reasons that give rise to otitis externa, most of whichare bacterial infection-related and some are fungal infection-related ordue to non-infectious skin diseases. When suffering from otitis externa,the patient usually has the following major symptoms: severe itching,swelling and pain of the external ear canal, as well as thick, white oryellow exudate. If the ear canal is blocked by the exudate, partialhearing loss will occur.

Under normal physiological conditions, mucus produced by the mucosa ofnasal cavity can attract substances, such as dust, pollen and powder, aswell as microbes, such as bacteria and viruses, and the like. The mucuscan flow out from the front part of the nose or flow down from the rearpart of the throat. When the nasal mucosa is subject to irritation orinflammation, excess mucus is produced which cannot be removed timely,so that nasal obstruction, runny nose, itching and/or sneezing arecaused.

Normal paranasal sinuses are air cavities in craniofacial bones aroundthe nasal cavity and comprise four pairs in total, namely maxillarysinuses, frontal sinuses, ethmoidal sinuses and sphenoidal sinuses. Themucosa is on the inner wall of each sinus and the sinuses respectivelyhave certain parts, shapes and outlets. When suffering from sinusitis,the patient has mucosal congestion and swelling and a lot ofmucopurulent or purulent nasal in the nasal cavity, resulting in severenasal obstruction, purulent nasal, headache, dizziness and decreasedsense of smell.

Lower respiratory tract inflammation mainly includes bronchitis, chronicbronchitis, pneumonia, bronchiectasis and the like. The main symptomsinclude cough, expectoration, asthma, chest pain, fever and the like. Atpresent, antibiotics and antitussive and expectorant medicines arecommonly used in clinical treatment.

Xeromycteria is a nasal disease that is mainly characterized by drynessin the nasal cavity. Rhinitis sicca in modern medicine is a chronicinflammatory disease of the nasal cavity, which is mainly represented asdryness of the nasal mucosa and reduction in nasal secretions. Thesymptoms include intranasal dryness, reduction in nasal secretions andprickling sensation or foreign body sensation in the nose, which oftenresult in sneezing and burning sensations. The patient is often inducedto pick the nose which can further cause a small amount of nasalbleeding, while the sense of smell is not generally impaired. The mucosain the front bottom area of nasal septum is often erosive, small-piecethin scabs can be attached on the mucosa and bleeding often occurs afterthe small-piece thin scabs are removed. While the causes are not cleartill now, it is generally believed that the disease is related to aindoor environment and external climate, and vitamin deficiency, anemia,heavy smoking and drinking can cause the change of the nasal mucosa andfurther cause the disease. As for the treatment of the disease, alubricating liquid medicine can be partially dropped in the nose and thepatient can be supplemented with vitamin A, vitamin B2, vitamin C,vitamin E and the like to enhance nutrition intake and balance.

Xerophthalmia is a general name of a variety of diseases, which causeabnormalities or dynamic abnormalities of quality or quantity of tearsdue to any reasons, reduce the stability of tear films and areaccompanied by ocular discomfort and/or ocular surface tissue lesioncharacteristics. Xerophthalmia is also known as keratoconjunctivitissicca. The common symptoms include dry eyes, fatigue, eye itching,foreign body sensations, burning heat sensations, thick secretions, fearof wind, photophobia and sensitivity to external stimuli. Sometimes, theeyes are too dry and lack basic tears, but the secretion of reflex tearsis stimulated, thereby often causing tearing. In more severe cases, theeyes turn red, swollen, congested and keratinized, and cornealepithelium is broken and adhered with filaments. Such injuries can causecorneal and conjunctival lesions over time, which can further affectvision.

The tear film is mainly composed with phospholipid, protein, mucin,electrolyte and water. The ingredients of a lipid layer are mainly frommeibomian gland, when in blinking (winking), lipids are compressed byeyelid, aggregated on a lower corneal water layer and dispersed like ahorizontal belt. At the end of blinking (winking), the lipids arerapidly spread on the water liquid layer at a speed greater than thespeed of eyelid open. The water layer is not directly exposed in air,and the evaporation of the tears is reduced. At present, literaturesreport that the most common reason causing dry eyes is meibomian glanddysfunction (MGD), which can affect the functions of the tear films andcause dry eyes. (Foulks, 2007 Surv Ophthalmol. July-August (4): 369-74;Xiao, et al. 2012 Chinese Journal of Ophthalmology. March, 48(3):282-5.)

At present, treatment methods for xerophthalmia mainly are artificialtears, inflammation inhibition, promotion of tears secretion and thelike. Treatment with artificial tears is the most common treatmentapproach, which is easiest to be accepted by patients. Commerciallyartificial tears are available, for example, Liposic (Bausch & Lomb),which contains the main ingredients of 1% medium chain triglyceride,0.2% carbomer 980, sorbitol, sodium hydroxide and the like, as well as apreservative, namely 0.01% cetrimide; and Refresh Dry Eye Therapy(formerly known as Refresh Endura, Allergan), which contains the mainingredients of 1% polysorbate 80, 1% glycerol, carbomer, castor oil,mannitol, sodium hydroxide and the like.

Xerostomia is a symptom caused by saliva deficiency in mouth. Theproduction and secretion of saliva are affected by various systemic,local, external and personal factors. As the secretion of saliva isreduced, the patient can feel xerostomia, foreign body sensations andburning sensations. When the patient chews food, especially relativelydry food, alimentary bolus cannot be formed, and swallowing is affected.Saliva secretion is insufficient, the washing effect to teeth and oralmucosa is also decreased, and the self-cleaning effect of the oralcavity becomes poor. As a result, a patient with xerostomia also hasrelatively high dental caries rate. Since xerostomia also affects thesense of taste, the appetite cannot be effectively stimulated, and thefunctions of a whole digestive system can also be affected.

At present, the treatment for xerostomia includes treatment against thecauses of the disease and the symptoms. The treatment against the causesof the disease is most effective when the causes of the disease areclear. Taking medicine-induced dry mouth as an example, the dry mouthcan be relieved by adjusting the medicines and the dosage thereof. Asfor dry mouth caused by increased consumption of saliva, reducing oreliminating mouth breathing can help. If dry mouth is caused bysubstantial destruction of salivary glands, such as radiotherapy of amalignant tumor at head and neck and Sjogren's syndrome, the dry mouthis currently mainly relieved by symptomatic treatment, and complicationsare further reduced.

Through the above description, it is clear that common characteristicsof these diseases are that liquid secreted by the mucosa of the cavitycanal is either increased and cannot be discharged timely due toinfections or inflammation of the cavity canal (ears or nose), thecavity canal is blocked, and ear congestion, nasal congestion, pain,cough and other discomfortable symptoms are further caused. Or, dryeyes, dry mouth, dry nose, asthma and other discomfortable symptoms arecaused by reduction of the secretions (nasal secretions, tear films andsaliva) at the corresponding parts or decreased stability due to changesin the compositions of normal secretions.

At present, in clinical treatment, antibiotics, steroids and surgicaltreatment are commonly used. These treatment methods with the exceptionof surgery, however, cannot rapidly relieve ear congestion, nasalcongestion, pain, cough, asthma, dry eyes, dry mouth, dry nose and otherdiscomfortable symptoms of the patient in a short time (minutes-hours).

Therefore, an urgent unmet need exists for a product that caneffectively relieve ear congestion, nasal congestion, pain, cough,asthma, dry eyes, dry mouth, dry nose and other discomfortable symptomsof the patients in a short time.

SUMMARY OF THE INVENTION

Technical problem to be solved by the invention includes providingcompositions and medicament delivery devices, and methods for preparingand using the same, which can effectively treat ear congestion, nasalcongestion, pain, cough, asthma, dry eyes, dry mouth, dry nose and otherdiscomfortable diseases and conditions in a short time.

The technical scheme adopted for solving the above technical problem isas follows.

In the past decades, people have attempted to utilize surfactants tosolve the problems of otitis media, rhinitis and the like. There were,however, various problems emerged in developing effective products. Forexample, although a nasal wash product prepared by utilizing syntheticsurfactants as ingredients could help the patient clear away mucus innasal cavity and reduce nasal congestion symptom effectively, theingredients in the product caused some patients to lose their sense ofsmell, which resulted a voluntary recall of the product from the market(NeilMed's SinuSurf Additive Causes Loss of Sense of Smell,http://www.texassinuscenter.com, accessed on Jul. 30, 2014).

Jang, et al. reported the effects of the nebulized pulmonary surfactantin a guinea pig otitis media model (Jang, et al. 2010 Int J PediatrOtorhinolaryngol. January 74(1):71-4.). The pulmonary surfactant used inthe study was expensive, and a nebulizer is complex and inconvenient touse in many settings. Chandrasekha, et al. reported that the aerosolizedsurfactant was used in animal experiments for treatment of otitis media(Chandrasekha, et al. 2004 Laryngoscope. March 114(3):472-85). Theformulation adopted there needed to employ a propellant, and the activeingredient existed in a solid form. Thus, in order to achieve thecurative effect, the formulation must be moistened first and adhered toa target part to increase the onset time. Meanwhile, the propellant maycause irritation to the nasal cavity with local inflammation.

The invention provides a formulation, including a containment vessel anda liquid formulation composition contained in the containment vessel,wherein the liquid formulation composition is an emulsion including asolvent and liquid particles which contain surfactants and are dispersedin the solvent. The volume average particle size of the liquid particlesis less than about 100 μm; the surface tension of the liquid formulationcomposition is less than about 60 mN/m and the absolute value of zetapotential of the liquid formulation composition is greater than about 15mV; and the containment vessel is a sprayer or a dropping device.

When the liquid formulation composition disclosed herein is applied tothe nasal cavity, the surfactant spreads on the nasal mucosa and gets incontact with the Eustachian tube opening in the back of nose. Thesurfactant further contacts with the surface of middle ear effusion. Asthe surface tension of the liquid formulation composition is relativelylow (less than 60 mN/m), the surface tension of exudate at the mucosa ofthe Eustachian tube can be rapidly reduced, and the Eustachian tube canbe opened more easily. Meanwhile, the liquid formulation composition isadhered on the mucosa of a cavity canal, and the lubricating effect isproduced. As a result, the middle ear effusion can flow out smoothly. Byeliminating the effusion and opening up the Eustachian tube, the earpressure can be equalized, eliminating or aliviating the symptoms oftinnitus and headache. Meanwhile, the risk of infection is reduced, theelimination of inflammation is accelerated, and the healing time isshortened.

For the pus in external ear canal, on the one hand, the liquidformulation composition can reduce the surface tension of the pus. Onthe other hand, the liquid formulation composition adheres to the mucosaof the external ear canal so as to produce the lubricating effect,promoting the smooth outflow of the pus thereby reduce the symptoms ofear congestion and ear swelling. Based on the same mechanism of action,the liquid formulation composition can adhere to the surface of themucosa of the nasal cavity, further promoting the clearing of the mucusin the nasal cavity and reducing the symptom of nasal congestion.

As known to the skilled artisan, one end of the Eustachian tube enterstympanic cavity from the front wall, the other end of the Eustachiantube enters nasopharynx, and the position is very hidden and is notconductive to treatment. The liquid formulation composition disclosedherein can be applied in a form of spray through a sprayer toeffectively deliver the formulation to the Eustachian tube, the nasalcavity, paranasal sinuses and other target parts to realize the curativeeffect, or be applied to the external ear canal and the nasal cavity inthe form of ear drops and nasal drops.

The treatment for lower respiratory tract inflammation of the inventionis mainly as follows: the surfactant can reach trachea through thesprayer, moisten the trachea, reduce the irritation of the disease tothe mucosa of the trachea, dilute sputum, easily cough out the sputum,reduce the surface tension of lung and relieve asthma. The formulationadopting the natural surfactant lecithin can moisten the trachea, reducethe surface tension of the lung, and repair the damaged mucosa.

The treatment for xeromycteria (or rhinitis sicca) of the invention ismainly as follows: the surfactant can effectively reach the nasal cavitythrough the sprayer or in the form of nasal drops, reduce the surfacetension of the nasal cavity and the mucus and make up for a lack ofliquid. The formulation prepared by adopting the natural surfactantlecithin can not only moisten the nasal cavity, but also repair thedamaged mucosa.

The treatment for xerophthalmia of the invention is mainly as follows:by utilizing the property of nature surfactant for reducing the surfacetension of the surfactant, the thickness of a tear lipid layer isincreased to keep the stability of tear films, which can prolong thebreak-up time of the tear films, reduce the evaporation of tears andkeep the quantity of ocular surface tears. The formulation prepared byadopting the natural surfactant lecithin can make up for the lack oflecithin in the tear lipid layer.

Research results show that the surface tension of the saliva in the oralcavity of the patient with xerostomia is discernibly higher than that ofnormal people (Cassie, et al. 2008 Sleep, Vol. 31, No. 3. “Upper AirwaySurface Tension but not Upper Airway Collapsibility is Elevated inPrimary Sjogren's Syndrome”). The surfactant in the invention can reducethe surface tension of the saliva of the patient with xerostomia, whilesimultaneously supplement saliva and relieve the symptom of dry mouth.

Compared to the aerosol and nebulization therapy, spraying does not needto utilize the propellant or the complex nebulizer. It uses a nasalspray device with the help of power produced by compressed air and sprayout the mist particles to make a water type spray. Spraying has theadvantages that the mist particles, which are sprayed out are thinner,are uniformly dispersed in the nasal cavity, less prone to loss, high inadhesion speed and allows rapid onset of action. Furthermore, thesprayer is less costly and has less stringent conditions for effectiveuse. When spraying is the adopted form or treatment, the stability ofthe formulation is critical. In particular, sedimentation and the likein the formulation is undesirable and must be prevented or minimized.

Through extensive research and development, it is found that the liquidformulation composition disclosed herein is a stable emulsion orsolution, which includes a liquid solvent and liquid particles dispersedin the solvent, wherein the liquid particles include a surfactant withdesirable surface activity. Furthermore, the absolute value of zetapotential of the liquid formulation composition is greater than about 15mV, and the volume average particle size of the liquid particles is lessthan about 100 μm. The liquid particles with the above characteristicscan be stably dispersed in the solvent. The sedimentation phenomenon ofthe solid powder surfactant, which is easy to occur, can be avoided.

The liquid formulation composition is a colloidal dispersion systemformed by the surfactant in the solvent. The zeta potential is animportant indicator characterizing the stability of the dispersionsystem. On the premise that the volume average particle size of theliquid particles of the liquid formulation composition is less thanabout 100 μm, the absolute value of zeta potential of the liquidformulation composition is more than about 15 mV. The dispersion systemwith the above characteristics can remain relatively stable and is lessprone to coagulation or agglomeration.

Meanwhile, when the liquid formulation composition is used in the sprayform, the liquid particles having the surfactant and the solvent aresprayed together out of a sprayer in the form of mist droplets. When theliquid formulation composition is used in the form of nasal drops, theliquid formulation composition directly enters the nasal cavity. Forexample, after the liquid formulation composition reaches the Eustachiantube, the nasal cavity, the paranasal sinuses and other target parts,the liquid surfactant is directly dispersed on the mucosa of Eustachiantube and becomes in contact with middle ear effusion and nasal mucus.This causes a reduction in the surface tension of the middle eareffusion and the nasal mucus. The liquid surfactant is simultaneouslyadhered to the surface of the mucosa giving rise to a lubricatingeffect. Together, these help smoothly clear away the middle ear effusionand the nasal mucus, resulting in rapid relief of the discomfortablesymptoms of the patient.

In addition, the liquid formulation composition disclosed herein hasgood stability, the main ingredients are from FDA's Generally RecognizedSafe (GRAS) list, and the surfactant exists in the solvent in a liquidform. When the liquid formulation composition is used in the spray form,the requirements on spray pressure and other using conditions are low,and the liquid formulation composition only needs to adopt theconventional sprayer and does not need to adopt the propellant or thespecial nebulizer. Furthermore, the dissolution process which isnecessary for the solid surfactant is not required for the liquidformulation at target sites, so the effectiveness can be achievedquickly; in addition, the liquid formulation composition does not needother substances to accelerate the dissolution at the target part.

Furthermore, in the liquid formulation composition disclosed herein, oneof medicines for treating rhinitis, sinusitis, lower respiratory tractinflammation, otitis media, otitis externa, xerostomia, xerophthalmiaand xeromycteria, or a combination thereof can be simultaneously addedto perform targeted treatment against rhinitis, sinusitis, otitis media,otitis externa, lower respiratory tract inflammation, xerostomia,xerophthalmia and xeromycteria.

Therefore, in one aspect, the invention generally relates to a liquidformulation composition. The liquid formulation composition includes asolvent and a surfactant dissolved in the solvent. The liquidformulation composition is characterized by a surface tension of lessthan about 60 mN/m, and a pH value from about 5.0 to about 7.4.

In another aspect, the invention generally relates to a liquidformulation composition. The liquid formulation composition includes asolvent and liquid particles dispersed in the solvent, wherein theliquid particles include a surfactant. The liquid formulationcomposition is an emulsion. The volume average particle size of theliquid particles is less than about 100 μm. The liquid formulationcomposition is characterized by a surface tension of less than about 60mN/m and an absolute value of zeta potential of greater than about 15mV.

In yet another aspect, the invention generally relates to a liquidformulation composition. The liquid formulation composition includes: anactive pharmaceutical ingredient; a solvent; and liquid formulation, theliquid formulation comprising a surfactant. The active pharmaceuticalingredient is selected from one of medicines for treating rhinitis,sinusitis, lower respiratory tract inflammation, otitis media, otitisexterna, xerostomia, xerophthalmia, xeromycteria, or a combinationthereof. The liquid formulation composition is characterized by asurface tension of less than about 60 mN/m, and a pH value from about5.0 to about 7.4.

In yet another aspect, the invention generally relates to a liquidformulation composition. The liquid formulation composition includes: anactive pharmaceutical ingredient; a solvent; and liquid particlesdispersed in the solvent, the liquid particles including a surfactant.The liquid formulation composition is an emulsion. The volume averageparticle size of the liquid particles is less than about 100 μm. Theactive pharmaceutical ingredient is selected from one of medicines fortreating rhinitis, sinusitis, lower respiratory tract inflammation,otitis media, otitis externa, xerostomia, xerophthalmia, xeromycteria,or a combination thereof. The liquid formulation composition ischaracterized by a surface tension of less than about 60 mN/m and anabsolute value of zeta potential of greater than about 15 mV.

In yet another aspect, the invention generally relates to a medicamentdelivery device. The medicament delivery device includes: a containmentvessel for holding a liquid including an outlet and a liquid formulationcomposition held in the containment vessel. The liquid formulationcomposition is a solution and includes a solvent and a surfactant. Theliquid formulation composition is characterized by a surface tension ofless than about 60 mN/m, and a pH value from about 5.0 to about 7.4.

In yet another aspect, the invention generally relates to a medicamentdelivery device. The medicament delivery device includes: a containmentvessel for holding a liquid including an outlet and a liquid formulationcomposition held in the containment vessel. The liquid formulationcomposition is an emulsion and includes a solvent and, dispersedtherein, liquid particles including a surfactant. The volume averageparticle size of the liquid particles is less than about 100 μm. Theliquid formulation composition is characterized by a surface tension ofless than about 60 mN/m and an absolute value of zeta potential ofgreater than about 15 mV.

In yet another aspect, the invention generally relates to a method forpreparing a liquid formulation composition. The method includes: (S1)dissolving or dispersing a surfactant in a solvent to form a solution ora stable suspension; and (S2) adjusting the solution to form a liquidformulation composition characterized by a surface tension of less thanabout 60 mN/m and a pH value from about 5.0 to about 7.4.

In yet another aspect, the invention generally relates to a method forpreparing a liquid formulation composition. The method includes: (S1)dissolving or dispersing a surfactant in a solvent with ultrasound ofabout 40 KHz to about 60 KHz for about 1 minute to about 3 minutes; and(S2) uniformly mixing an active pharmaceutical ingredient, thesurfactant and a solvent under a stirring condition characterized by arotational speed of more than 3000 rpm to form a liquid formulationcomposition characterized by a surface tension of less than about 60mN/m and an absolute value of zeta potential of greater than about 15mV.

In yet another aspect, the invention generally relates to a method forpreparing the liquid formulation composition. The method includes: (S1)dissolving or dispersing a surfactant in a solvent with ultrasound ofabout 40 KHz to about 60 KHz for about 1 minute to about 3 minutes; and(S2) uniformly mixing an active pharmaceutical ingredient, thesurfactant and a solvent under a stirring condition characterized by arotational speed of more than 3000 rpm to form a liquid formulationcomposition in the form of an emulsion. The liquid formulationcomposition includes a solvent and, dispersed therein, liquid particlesincluding a surfactant. The volume average particle size of the liquidparticles is less than about 100 The liquid formulation composition ischaracterized by a surface tension of less than about 60 mN/m and anabsolute value of zeta potential of more than about 15 mV. The activepharmaceutical ingredient is selected from one of medicines for treatingrhinitis, sinusitis, lower respiratory tract inflammation, otitis media,otitis externa, xerostomia, xerophthalmia, xeromycteria, or acombination thereof.

In yet another aspect, the invention generally relates to a method forpreparing the medicament delivery device. The method include: (S1)dissolving or dispersing a surfactant in a solvent with ultrasound ofabout 40 KHz to about 60 KHz for about 1 minute to about 3 minutes; and(S2) uniformly mixing the surfactant with a solvent under a stirringcondition characterized by a rotational speed of more than 3000 rpm toform a liquid formulation. The liquid formulation composition is anemulsion and includes a solvent and, dispersed therein, liquid particlesincluding a surfactant. The volume average particle size of the liquidparticles is less than about 100 The liquid formulation composition ischaracterized by a surface tension of less than about 60 mN/m and anabsolute value of zeta potential of more than about 15 mV; and (S3)filling the liquid formulation composition into a containment vessel.

In yet another aspect, the invention generally relates to a method fortreating, reducing, or preventing otitis media. The method includesadministering to a subject in need thereof a liquid formulationcomposition disclosed herein, in an amount effective to treat, prevent,or reduce one or more diseases or disorders selected from rhinitis,sinusitis, lower respiratory tract inflammation, otitis media, otitisexterna, xerostomia, xerophthalmia and xeromycteria.

In yet another aspect, the invention generally relates to a method fortreating, reducing, or preventing otitis media. The method includesadministering to a subject in need thereof a liquid formulationcomposition, using the medicament delivery device disclosed herein, inan amount effective to treat, prevent, or reduce one or more diseases ordisorders selected from rhinitis, sinusitis, lower respiratory tractinflammation, otitis media, otitis externa, xerostomia, xerophthalmiaand xeromycteria.

In yet another aspect, the invention generally relates to a method fortreatment of otitis media using the liquid formulation composition ofthe invention.

In yet another aspect, the invention generally relates to a method fortreatment of otitis externa using the liquid formulation composition ofthe invention.

In yet another aspect, the invention generally relates to a method fortreatment of rhinitis using the liquid formulation composition of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of sinusitis using the liquid formulation composition of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of xerostomia using the liquid formulation composition of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of xerophthalmia using the liquid formulation composition ofthe invention.

In yet another aspect, the invention generally relates to a method fortreatment of xeromycteria using the liquid formulation composition ofthe invention.

In yet another aspect, the invention generally relates to a method fortreatment of lower respiratory tract inflammation using the liquidformulation composition of the invention.

In yet another aspect, the invention generally relates to a method fortreatment of otitis media using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of otitis externa using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of rhinitis using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of sinusitis using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of xerostomia using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of xerophthalmia using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of xeromycteria using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of lower respiratory tract inflammation using the medicamentdelivery device of of the invention.

Thus, as disclosed herein, the liquid formulation compositions can beused through the nasal cavity for adjuvant treatment of rhinitis,sinusitis, lower respiratory tract inflammation, otitis media andxeromycteria; the liquid formulation compositions can be used throughthe oral cavity for adjuvant treatment of dry mouth caused by variousreasons and lower respiratory tract inflammation; and the liquidformulation compositions can be used through eyes for adjuvant treatmentof dry eyes.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a sedimentation stability comparison of Example II, Example IVand Comparative example II in the test of sedimentation stability of theinvention.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

As used herein, the term “effective amount” of an active agent refers toan amount sufficient to elicit the desired biological response. As willbe appreciated by those of ordinary skill in this art, the effectiveamount of a compound of the invention may vary depending on such factorsas the desired biological endpoint, the pharmacokinetics of thecompound, the disease being treated, the mode of administration, and thepatient.

As used herein, the term “treating, reducing, or preventing a metabolicdisorder” refers to ameliorating such a condition before or after it hasoccurred. As compared with an equivalent untreated control, suchreduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%,60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

As used herein, the term “pharmaceutically acceptable excipient,carrier, or diluent” refers to a pharmaceutically acceptable material,composition or vehicle, such as a liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting the subject pharmaceutical agent from one organ, or portionof the body, to another organ, or portion of the body. Each carrier mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not injurious to the patient. Someexamples of materials which can serve as pharmaceutically-acceptablecarriers include: sugars, such as lactose, glucose and sucrose;starches, such as corn starch and potato starch; cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients,such as cocoa butter and suppository waxes; oils, such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols, such as propylene glycol; polyols, such asglycerin, sorbitol, mannitol and polyethylene glycol; esters, such asethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; and other non-toxic compatible substances employed inpharmaceutical formulations. Wetting agents, emulsifiers and lubricants,such as sodium lauryl sulfate, magnesium stearate, and polyethyleneoxide-polypropylene oxide copolymer as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

As used herein, the term “subject” refers to any animal (e.g., amammal), including, but not limited to humans, non-human primates,rodents, and the like, which is to be the recipient of a particulartreatment. Typically, the terms “subject” and “patient” are usedinterchangeably herein in reference to a human subject.

DETAILED DESCRIPTION OF THE INVENTION

In order to make the technical problem solved by the invention, thetechnical scheme and the beneficial effects to be more clearlyunderstood, the invention is further described in detail withcombination of figures and embodiments. It should be understood that thespecific embodiments described herein are only used for explaining theinvention rather than limiting the invention.

In one aspect, the invention generally relates to a liquid formulationcomposition. The liquid formulation composition includes a solvent and asurfactant dispersed or dissolved in the solvent to form a solution or astable suspension. The liquid formulation composition is characterizedby a surface tension of less than about 60 mN/m, and a pH value fromabout 5.0 to about 7.4.

In certain embodiments of the liquid formulation composition, thesolvent includes one of water, ethanol, glycerol, medical silicone oiland edible vegetable oil, or a combination thereof. In certain preferredembodiments, the solvent includes water.

In certain embodiments, the surface tension of the liquid formulationcomposition is less than about 40 mN/m (e.g., less than about 35 mN/m,less than about 30 mN/m, less than about 27 mN/m, less than about 25mN/m).

In certain embodiments, the pH value of the liquid formulationcomposition is from about 6.0 to about 7.4 (e.g., about 6.0, 6.2, 6.4,6.6, 6.8, 7.0, 7.2, 7.4).

The surfactant(s) utilized in a liquid formulation composition of theinvention may be any suitable surfactant, for example, a naturalsurfactant or a synthetic surfactant, or a combination thereof.

Exemplary surfactants include natural phospholipid, sterol, pulmonarysurfactant, stearic acid, oleic acid, lauric acid, benzalkoniumchloride, benzalkonium bromide, cetrimide, sorbitan fatty acid,polysorbate, polyoxyethylene stearate, polyoxyethylene-fatty alcoholether, poloxamer, dipalmitoyl phosphatidylcholine, cholesterol,cholesteryl ester, phosphatidyl ethanolamine, phosphatidylglycerol,phosphatidylserine, polyethylene glycol, or a combination thereof.

In certain embodiments, the surfactant includes one of lecithin, sterol,pulmonary surfactant, poloxamer, dipalmitoyl phosphatidylcholine,cholesterol, cholesteryl ester, phosphatidyl ethanolamine,phosphatidylglycerol, phosphatidylserine, polyethylene glycol,phosphatidylserine, or a combination thereof.

In certain embodiments of the liquid formulation composition, thecontent of the surfactant is in the range from about 0.0001 wt % toabout 25.0 wt %, and the content of the solvent is in the range fromabout 75.0 wt % to about 99.9999 wt %.

In certain embodiments, the liquid formulation composition includes anactive pharmaceutical ingredient, wherein the active pharmaceuticalingredient is selected from one of medicines for treating rhinitis,sinusitis, lower respiratory tract inflammation, otitis media, otitisexterna, xerostomia, xerophthalmia, xeromycteria, or a combinationthereof.

Any suitable active pharmaceutical ingredients may be utilized. Forexample active pharmaceutical ingredient of the liquid formulationcomposition may include one of cortisone, hydrocortisone,beclomethasone, triamcinolone acetonide, mometasone, dexamethasone,fluocinolone acetonide, budesonide, fluticasone, ephedrinehydrochloride, xylometazoline hydrochloride, levocabastinehydrochloride, azelastine hydrochloride, fructus xanthii, dandelion,radix scutellariae, bitter gourd, herba ephedrae, flos magnoliae, herbaasari, radix angelicae dahuricae, rhizome acori tatarinowii, catechu,Longjing tea, cortex phellodendri, ofloxacin, levofloxacin, norfloxacin,lomefloxacin, tosufloxacin, sparfloxacin, roxithromycin, chloromycetin,penicillin, clindamycin, nitrofurazone, amoxicillin, ampicillin,clavulanate potassium, cefaclor, cefixime, cefdinir, cephradine,cephalexin, cefpodoxime, cefuroxime axetil, cefprozil, azithromycin,minocycline, acetyl midecamycin, acetylspiramycin, metronidazole, musk,potassium aluminium sulfate anhydrous, calamine, borneol, cochineal,cacumen platycladi, echinacea root, baptisia tinctoria root,D-panthenol, glycerin, hyaluronic acid, butanediol, polyethylene glycol,propanediol, hexanediol, xylitol, sorbitol, or a combination thereof.

In certain embodiments of the liquid formulation composition, thecontent of the surfactant is in the range from about 0.0001 wt % toabout 25.0 wt %, the content of the solvent is in the range from about70.0 wt % to about 99.9989 wt %, and the content of the activepharmaceutical ingredient is in the range from about 0.001 wt % to about5.0 wt %.

The liquid formulation composition of the invention may further includeone of bacteriostatic agent, flavoring agent, stabilizer, antioxidant,or a combination thereof.

In certain embodiments of the liquid formulation composition, thebacteriostatic agent includes one of parabens or its salts, benzoic acidor its salts, benzyl alcohol, phenylethanol, phenylacetic acid,phenoxyethanol, lauric acid monoglyceride, chlorobutanol, sorbic acid orits salts, calcium propionate, sodium propionate, dehydroacetic acid orits salts, sodium diacetate, benzalkonium chloride, benzalkoniumbromide, cetrimide, chlorhexidine acetate, propanediol, carbon dioxide,nisin, natamycin, momordicin, thimerosal, mercuric nitrate, or acombination thereof.

In certain embodiments of the liquid formulation composition, theflavoring agent includes one of menthol, borneol, lemon oil, patchoulioil, cinnamon oil, jujube tincture, vanillin, peppermint oil, rose oil,eucalyptus oil, spearmint oil, eugenol, citral, jasmine extract,chrysanthemum extract, osmanthus extract, benzyl alcohol, phenylethanol,terpineol, methyl cyclopentenolone, α-amyl cinnamic aldehyde, butyricacid, hexanoic acid, isoamyl acetate, benzyl acetate, linalyl acetate,ethyl propionate, ethyl butyrate, isoamyl butyrate, benzyl butyrate,isoamyl isovalerate, ethyl hexanoate, ethyl heptanoate, ethyl lactate,allyl hexanoate, γ-nonalactone, ethyl maltol, allyl cyclohexylpropionate, maltol, γ-undecalactone, raspberry ketone, benzylpropionate, butyl butyrate, ethyl isovalerate, ethyl formate, benzylbenzoate, methyl pyrazine, 2,3-dimethyl pyrazine, trimethyl pyrazine,2-acetyl pyrazine, 4-methyl-5-(β-hydroxyethyl) thiazole, 2-acetylthiazole, 2,3,5,6-tetramethyl pyrazine, hexadecanal, ethyl vanillin,hydroxyl citronellal, or a combination thereof;

In certain embodiments of the liquid formulation composition, thestabilizer includes one of lecithin, poloxamer, saponin, tannin,glycerin fatty acid ester, sucrose fatty acid ester, propanediol fattyacid ester, cholesterol, cholesterol ester, polyethylene glycol,cellulose or its derivatives, dextrin, Arabic gum, tragacanth gum,pectin cellulose cheese, gelatin, alginic acid, or a combinationthereof.

In certain embodiments of the liquid formulation composition, theantioxidant includes one of tert-butyl hydroxy anisole, butylatedhydroxytoluene, tert-butyl hydroquinone, propyl gallate, ascorbylpalmitate, dilauryl thiodipropionate, 4-hexyl resorcinol, tocopherol,L-ascorbic acid, D-sodium erythorbate, tea polyphenols, rosemaryextract, ginger extract, sugar alcohols, amino acids, or a combinationthereof.

In certain embodiments of the liquid formulation composition, thecontent of the surfactant is in the range from about 0.0001 wt % toabout 25.0 wt %, the content of the solvent is in the range from about63.0 wt % to about 99.9879 wt %, the content of the bacteriostatic agentis in the range from about 0.001 wt % to about 2.0 wt %, the content ofthe flavoring agent is in the range from about 0.01 wt % to about 5.0 wt%, and the content of the antioxidant is in the range from about 0.001wt % to 5.0 wt %. In certain embodiments of the liquid formulationcomposition, the content of the surfactant is in the range from about0.0001 wt % to about 25.0 wt %, the content of the solvent is in therange from about 58.0 wt % to about 99.9869 wt %, the content of thebacteriostatic agent is in the range from about 0.001 wt % to about 2.0wt %, the content of the flavoring agent is in the range from about 0.01wt % to about 5.0 wt %, and the content of the antioxidant is in therange from about 0.001 wt % to 5.0 wt %, the content of the activepharmaceutical ingredient the content of which is in the range fromabout 0.001 wt % to about 5.0 wt %.

In another aspect, the invention generally relates to a liquidformulation composition. The liquid formulation composition includes asolvent and liquid particles dispersed in the solvent, wherein theliquid particles including a surfactant. The liquid formulationcomposition is an emulsion. The volume average particle size of theliquid particles is less than about 100 The liquid formulationcomposition is characterized by a surface tension of less than about 60mN/m and an absolute value of zeta potential of greater than about 15mV.

In certain embodiments of the liquid formulation composition, thesolvent includes one of water, ethanol, glycerol, medical silicone oiland edible vegetable oil, or a combination thereof. In certain preferredembodiments, the solvent includes water.

In certain embodiments, the absolute value of zeta potential of theliquid formulation composition is greater than about 20 mV (e.g., greatthan about 25 mV, great than about 30 mV, great than about 35 mV, greatthan about 40 mV, great than about 40 mV, great than about 45 mV, greatthan about 50 mV).

In certain embodiments of the liquid formulation composition, the volumeaverage particle size of the liquid particles is from about 50 nm toabout 100 μm (e.g., from about 100 nm to about 100 μm, from about 500 nmto about 100 μm, from about 1 μm to about 100 μm, from about 10 μm toabout 100 μm, from about 50 nm to about 50 μm, from about 50 nm to about10 μm, from about 50 nm to about 5 μm, from about 50 nm to about 1 μm).

In certain embodiments, the volume average particle size of the liquidparticles is from about 1 μm to about 100 μm (e.g., from about 1 μm toabout 10 μm, from about 5 μm to about 100 μm, from about 20 μm to about100 μm, from about 50 μm to about 100 μm, from about 1 μm to about 50μm, from about 1 μm to about 20 μm, from about 1 μm to about 10 μm). Incertain embodiments, the volume average particle size of the liquidparticles is from about 500 nm to about 1 μm. In certain embodiments,the volume average particle size of the liquid particles is from about50 nm to about 500 nm (e.g., from about 100 nm to about 500 nm, fromabout 200 nm to about 500 nm, from about 50 nm to about 300 nm, fromabout 50 nm to about 200 nm, from about 50 nm to about 100 nm).

In certain embodiments, the pH value of the liquid formulationcomposition is from about 5.0 to about 7.4 (e.g., from about 5.5 toabout 7.4, from about 6.0 to about 7.4, from about 7.0 to about 7.4,from about 5.0 to about 7.0, from about 5.0 to about 6.5, from about 5.0to about 6.0, from about 5.0 to about 5.5).

In certain embodiments, the surface tension of the liquid formulationcomposition is less than about 40 mN/m (e.g., less than about 35 mN/m,less than about 30 mN/m, less than about 27 mN/m, less than about 25mN/m).

The surfactant(s) utilized in a liquid formulation composition of theinvention may be any suitable surfactant, for example, a naturalsurfactant or a synthetic surfactant, or a combination thereof.

Exemplary surfactants include natural phospholipid, sterol, pulmonarysurfactant, stearic acid, oleic acid, lauric acid, benzalkoniumchloride, benzalkonium bromide, cetrimide, sorbitan fatty acid,polysorbate, polyoxyethylene stearate, polyoxyethylene-fatty alcoholether, poloxamer, dipalmitoyl phosphatidylcholine, cholesterol,cholesteryl ester, phosphatidyl ethanolamine, phosphatidylglycerol,phosphatidylserine, polyethylene glycol, or a combination thereof.

In certain embodiments, the surfactant includes one of lecithin, sterol,pulmonary surfactant, poloxamer, dipalmitoyl phosphatidylcholine,cholesterol, cholesteryl ester, phosphatidyl ethanolamine,phosphatidylglycerol, phosphatidylserine, polyethylene glycol, or acombination thereof.

In certain embodiments of the liquid formulation composition, thecontent of the surfactant is in the range from about 0.1 wt % to about25.0 wt %, and the content of the solvent is in the range from about75.0 wt % to about 99.9 wt %.

In certain embodiments, the liquid formulation composition furtherincludes one of bacteriostatic agent, flavoring agent, stabilizer,antioxidant, or a combination thereof.

In certain embodiments, the bacteriostatic agent includes one ofparabens or its salts, benzoic acid or its salts, benzyl alcohol,phenylethanol, phenylacetic acid, phenoxyethanol, lauric acidmonoglyceride, chlorobutanol, sorbic acid or its salts, calciumpropionate, sodium propionate, dehydroacetic acid or its salts, sodiumdiacetate, benzalkonium chloride, benzalkonium bromide, cetrimide,chlorhexidine acetate, propanediol, carbon dioxide, nisin, natamycin,momordicin, thimerosal, mercuric nitrate, or a combination thereof.

In certain embodiments, the flavoring agent includes one of menthol,borneol, lemon oil, patchouli oil, cinnamon oil, jujube tincture,vanillin, peppermint oil, rose oil, eucalyptus oil, spearmint oil,eugenol, citral, jasmine extract, chrysanthemum extract, osmanthusextract, benzyl alcohol, phenylethanol, terpineol, methylcyclopentenolone, α-amyl cinnamic aldehyde, butyric acid, hexanoic acid,isoamyl acetate, benzyl acetate, linalyl acetate, ethyl propionate,ethyl butyrate, isoamyl butyrate, benzyl butyrate, isoamyl isovalerate,ethyl hexanoate, ethyl heptanoate, ethyl lactate, allyl hexanoate,γ-nonalactone, ethyl maltol, allyl cyclohexyl propionate, maltol,γ-undecalactone, raspberry ketone, benzyl propionate, butyl butyrate,ethyl isovalerate, ethyl formate, benzyl benzoate, methyl pyrazine,2,3-dimethyl pyrazine, trimethyl pyrazine, 2-acetyl pyrazine,4-methyl-5-((3-hydroxyethyl) thiazole, 2-acetyl thiazole,2,3,5,6-tetramethyl pyrazine, hexadecanal, ethyl vanillin, hydroxylcitronellal, or a combination thereof;

In certain embodiments, the stabilizer includes one of lecithin,poloxamer, saponin, tannin, glycerin fatty acid ester, sucrose fattyacid ester, propanediol fatty acid ester, cholesterol, cholesterolester, polyethylene glycol, cellulose or its derivatives, dextrin,Arabic gum, tragacanth gum, pectin cellulose cheese, gelatin, alginicacid, or a combination thereof.

In certain embodiments, the antioxidant includes one of tert-butylhydroxy anisole, butylated hydroxytoluene, tert-butyl hydroquinone,propyl gallate, ascorbyl palmitate, dilauryl thiodipropionate, 4-hexylresorcinol, tocopherol, L-ascorbic acid, D-sodium erythorbate, teapolyphenols, rosemary extract, ginger extract, sugar alcohols, aminoacids, or a combination thereof.

In certain embodiments of the liquid formulation composition, thecontent of the surfactant is in the range from about 0.1 wt % to about25.0 wt %, the content of the solvent is in the range from about 58.0 wt% to about 99.878 wt %, the content of the bacteriostatic agent is inthe range from about 0.001 wt % to about 2.0 wt %, the content of theflavoring agent is in the range from about 0.01 wt % to about 5.0 wt %,the content of the stabilizer is in the range from about 0.01 wt % toabout 5.0 wt %, and the content of the antioxidant is in the range fromabout 0.001 wt % to 5.0 wt %.

In yet another aspect, the invention generally relates to a liquidformulation composition. The liquid formulation composition includes: anactive pharmaceutical ingredient; a solvent; and liquid particlesdispersed in the solvent, the liquid particles including a surfactant.The liquid formulation composition is an emulsion. The volume averageparticle size of the liquid particles is less than about 100 The activepharmaceutical ingredient is selected from one of medicines for treatingrhinitis, sinusitis, lower respiratory tract inflammation, otitis media,otitis externa, xerostomia, xerophthalmia, xeromycteria, or acombination thereof. The liquid formulation composition is characterizedby a surface tension of less than about 60 mN/m and an absolute value ofzeta potential of greater than about 15 mV.

In certain embodiments of the liquid formulation composition, thesolvent includes one of water, ethanol, glycerol, medical silicone oiland edible vegetable oil, or a combination thereof. In certain preferredembodiments, the solvent includes water.

In certain embodiments, the absolute value of zeta potential of theliquid formulation composition is greater than about 20 mV (e.g., greatthan about 25 mV, great than about 30 mV, great than about 35 mV, greatthan about 40 mV, great than about 40 mV, great than about 45 mV, greatthan about 50 mV).

In certain embodiments of the liquid formulation composition, the volumeaverage particle size of the liquid particles is from about 50 nm toabout 100 μm (e.g., from about 100 nm to about 100 μm, from about 500 nmto about 100 μm, from about 1 μm to about 100 μm, from about 10 μm toabout 100 μm, from about 50 nm to about 50 μm, from about 50 nm to about10 μm, from about 50 nm to about 5 μm, from about 50 nm to about 1 μm).

In certain embodiments, the volume average particle size of the liquidparticles is from about 1 μm to about 100 μm (e.g., from about 1 μm toabout 10 μm, from about 5 μm to about 100 μm, from about 20 μm to about100 μm, from about 50 μm to about 100 μm, from about 1 μm to about 50μm, from about 1 μm to about 20 μm, from about 1 μm to about 10 μm). Incertain embodiments, the volume average particle size of the liquidparticles is from about 500 nm to about 1 μm. In certain embodiments,the volume average particle size of the liquid particles is from about50 nm to about 500 nm (e.g., from about 100 nm to about 500 nm, fromabout 200 nm to about 500 nm, from about 50 nm to about 300 nm, fromabout 50 nm to about 200 nm, from about 50 nm to about 100 nm).

In certain embodiments, the pH value of the liquid formulationcomposition is from about 5.0 to about 7.4 (e.g., from about 5.5 toabout 7.4, from about 6.0 to about 7.4, from about 7.0 to about 7.4,from about 5.0 to about 7.0, from about 5.0 to about 6.5, from about 5.0to about 6.0, from about 5.0 to about 5.5).

In certain embodiments, the surface tension of the liquid formulationcomposition is less than about 40 mN/m (e.g., less than about 35 mN/m,less than about 30 mN/m, less than about 27 mN/m, less than about 25mN/m).

The surfactant(s) utilized in a liquid formulation composition of theinvention may be any suitable surfactant, for example, a naturalsurfactant or a synthetic surfactant, or a combination thereof.

Exemplary surfactants include natural phospholipid, sterol, pulmonarysurfactant, stearic acid, oleic acid, lauric acid, benzalkoniumchloride, benzalkonium bromide, cetrimide, sorbitan fatty acid,polysorbate, polyoxyethylene stearate, polyoxyethylene-fatty alcoholether, poloxamer, dipalmitoyl phosphatidylcholine, cholesterol,cholesteryl ester, phosphatidyl ethanolamine, phosphatidylglycerol,phosphatidylserine, polyethylene glycol, or a combination thereof.

In certain embodiments, the surfactant includes one of lecithin, sterol,pulmonary surfactant, poloxamer, dipalmitoyl phosphatidylcholine,cholesterol, cholesteryl ester, phosphatidyl ethanolamine,phosphatidylglycerol, phosphatidylserine, polyethylene glycol, or acombination thereof.

Any suitable active pharmaceutical ingredients may be utilized. Forexample active pharmaceutical ingredient of the liquid formulationcomposition may include one of cortisone, hydrocortisone,beclomethasone, triamcinolone acetonide, mometasone, dexamethasone,fluocinolone acetonide, budesonide, fluticasone, ephedrinehydrochloride, xylometazoline hydrochloride, levocabastinehydrochloride, azelastine hydrochloride, fructus xanthii, dandelion,radix scutellariae, bitter gourd, herba ephedrae, flos magnoliae, herbaasari, radix angelicae dahuricae, rhizome acori tatarinowii, catechu,Longjing tea, cortex phellodendri, ofloxacin, levofloxacin, norfloxacin,lomefloxacin, tosufloxacin, sparfloxacin, roxithromycin, chloromycetin,penicillin, clindamycin, nitrofurazone, amoxicillin, ampicillin,clavulanate potassium, cefaclor, cefixime, cefdinir, cephradine,cephalexin, cefpodoxime, cefuroxime axetil, cefprozil, azithromycin,minocycline, acetyl midecamycin, acetylspiramycin, metronidazole, musk,potassium aluminium sulfate anhydrous, calamine, borneol, cochineal,cacumen platycladi, echinacea root, baptisia tinctoria root,D-panthenol, glycerin, hyaluronic acid, butanediol, polyethylene glycol,propanediol, hexanediol, xylitol, sorbitol, or a combination thereof.

In certain embodiments of the liquid formulation composition, thecontent of the surfactant is in the range from about 0.1 wt % to about25.0 wt %; the content of the solvent is in the range from about 70.0 wt% to about 99.899 wt %; and the content of the active pharmaceuticalingredient is in the range from about 0.001 wt % to about 5.0 wt %.

In certain embodiments, the liquid formulation composition furtherincludes one of bacteriostatic agent, flavoring agent, stabilizer,antioxidant, or a combination thereof.

In certain embodiments, the bacteriostatic agent includes one ofparabens or its salts, benzoic acid or its salts, benzyl alcohol,phenylethanol, phenylacetic acid, phenoxyethanol, lauric acidmonoglyceride, chlorobutanol, sorbic acid or its salts, calciumpropionate, sodium propionate, dehydroacetic acid or its salts, sodiumdiacetate, benzalkonium chloride, benzalkonium bromide, cetrimide,chlorhexidine acetate, propanediol, carbon dioxide, nisin, natamycin,momordicin, thimerosal, mercuric nitrate, or a combination thereof.

In certain embodiments, the flavoring agent includes one of menthol,borneol, lemon oil, patchouli oil, cinnamon oil, jujube tincture,vanillin, peppermint oil, rose oil, eucalyptus oil, spearmint oil,eugenol, citral, jasmine extract, chrysanthemum extract, osmanthusextract, benzyl alcohol, phenylethanol, terpineol, methylcyclopentenolone, α-amyl cinnamic aldehyde, butyric acid, hexanoic acid,isoamyl acetate, benzyl acetate, linalyl acetate, ethyl propionate,ethyl butyrate, isoamyl butyrate, benzyl butyrate, isoamyl isovalerate,ethyl hexanoate, ethyl heptanoate, ethyl lactate, allyl hexanoate,γ-nonalactone, ethyl maltol, allyl cyclohexyl propionate, maltol,γ-undecalactone, raspberry ketone, benzyl propionate, butyl butyrate,ethyl isovalerate, ethyl formate, benzyl benzoate, methyl pyrazine,2,3-dimethyl pyrazine, trimethyl pyrazine, 2-acetyl pyrazine,4-methyl-5-(β-hydroxyethyl) thiazole, 2-acetyl thiazole,2,3,5,6-tetramethyl pyrazine, hexadecanal, ethyl vanillin, hydroxylcitronellal, or a combination thereof.

In certain embodiments, the stabilizer includes one of lecithin,poloxamer, saponin, tannin, glycerin fatty acid ester, sucrose fattyacid ester, propanediol fatty acid ester, cholesterol, cholesterolester, polyethylene glycol, cellulose or its derivatives, dextrin,Arabic gum, tragacanth gum, pectin cellulose cheese, gelatin, alginicacid, or a combination thereof; and

In certain embodiments, the antioxidant includes one of tert-butylhydroxy anisole, butylated hydroxytoluene, tert-butyl hydroquinone,propyl gallate, ascorbyl palmitate, dilauryl thiodipropionate, 4-hexylresorcinol, tocopherol, L-ascorbic acid, D-sodium erythorbate, teapolyphenols, rosemary extract, ginger extract, sugar alcohols, aminoacids, or a combination thereof.

In certain embodiments of the liquid formulation composition, thecontent of the surfactant is in the range from about 0.1 wt % to about25.0 wt %, the content of the solvent is in the range from about 53.0 wt% about 99.877 wt %, the content of the bacteriostatic agent is in therange from about 0.001 wt % to about 2.0 wt %, the content of theflavoring agent is in the range from about 0.01 wt % to about 5.0 wt %,the content of the stabilizer is in the range from about 0.01 wt % toabout 5.0 wt %, the content of the antioxidant is in the range fromabout 0.001 wt % to about 5.0 wt %, and the content of the activepharmaceutical ingredient is in the range from about 0.001 wt % to about5.0 wt %.

In yet another aspect, the invention generally relates to a medicamentdelivery device. The medicament delivery device includes: a containmentvessel for holding a liquid including an outlet and a liquid formulationcomposition held in the containment vessel. The liquid formulationcomposition is an emulsion and includes a solvent and, dispersedtherein, liquid particles including a surfactant. The volume averageparticle size of the liquid particles is less than about 100 μm. Theliquid formulation composition is characterized by a surface tension ofless than about 60 mN/m and an absolute value of zeta potential ofgreater than about 15 mV.

In certain embodiments of the medicament delivery device, thecontainment vessel is configured to function as a sprayer, allowingcontrolled spraying of the liquid formulation composition out of theoutlet.

In certain embodiments of the medicament delivery device, thecontainment vessel is configured to function as a dropping device,allowing controlled dropping of the liquid formulation composition outof the outlet.

In certain embodiments of the medicament delivery device, the absolutevalue of zeta potential of the liquid formulation composition is greaterthan about 20 mV (e.g., great than about 25 mV, great than about 30 mV,great than about 35 mV, great than about 40 mV, great than about 40 mV,great than about 45 mV, great than about 50 mV).

In certain embodiments of the medicament delivery device, the volumeaverage particle size of the liquid particles is from about 50 nm toabout 100 μm (e.g., from about 100 nm to about 100 μm, from about 500 nmto about 100 μm, from about 1 μm to about 100 μm, from about 10 μm toabout 100 μm, from about 50 nm to about 50 μm, from about 50 nm to about10 μm, from about 50 nm to about 5 μm, from about 50 nm to about 1 μm).

In certain embodiments of the medicament delivery device, the volumeaverage particle size of the liquid particles is from about 1 μm toabout 100 μm (e.g., from about 1 μm to about 10 μm, from about 5 μm toabout 100 μm, from about 20 μm to about 100 μm, from about 50 μm toabout 100 μm, from about 1 μm to about 50 μm, from about 1 μm to about20 μm, from about 1 μm to about 10 μm). In certain embodiments, thevolume average particle size of the liquid particles is from about 500nm to about 1 μm. In certain embodiments, the volume average particlesize of the liquid particles is from about 50 nm to about 500 nm (e.g.,from about 100 nm to about 500 nm, from about 200 nm to about 500 nm,from about 50 nm to about 300 nm, from about 50 nm to about 200 nm, fromabout 50 nm to about 100 nm).

In certain embodiments of the medicament delivery device, the pH valueof the liquid formulation composition is from about 5.0 to about 7.4(e.g., from about 5.5 to about 7.4, from about 6.0 to about 7.4, fromabout 7.0 to about 7.4, from about 5.0 to about 7.0, from about 5.0 toabout 6.5, from about 5.0 to about 6.0, from about 5.0 to about 5.5).

In certain embodiments of the medicament delivery device, the surfacetension of the liquid formulation composition is less than about 40 mN/m(e.g., less than about 35 mN/m, less than about 30 mN/m, less than about27 mN/m, less than about 25 mN/m).

In certain embodiments of the medicament delivery device, the surfactantis a natural surfactant or a synthetic surfactant, or a combinationthereof.

Exemplary surfactant includes one of natural phospholipid, sterol,pulmonary surfactant, stearic acid, oleic acid, lauric acid,benzalkonium chloride, benzalkonium bromide, cetrimide, sorbitan fattyacid, polysorbate, polyoxyethylene stearate, polyoxyethylene-fattyalcohol ether, poloxamer, dipalmitoyl phosphatidylcholine, cholesterol,cholesteryl ester, phosphatidyl ethanolamine, phosphatidylglycerol,phosphatidylserine, polyethylene glycol, or a combination thereof.

In certain embodiments of the medicament delivery device, the surfactantincludes one of lecithin, sterol, pulmonary surfactant, poloxamer,dipalmitoyl phosphatidylcholine, cholesterol, cholesteryl ester,phosphatidyl ethanolamine, phosphatidylglycerol, phosphatidylserine,polyethylene glycol, or a combination thereof.

Any suitable solvent may be utilized. In certain embodiments of themedicament delivery device, the solvent is one of water, ethanol,glycerol, medical silicone oil and edible vegetable oil, or acombination thereof.

In certain embodiments of the medicament delivery device, in the liquidformulation composition, the content of the surfactant is in the rangefrom about 0.1 wt % to about 25.0 wt %, and the content of the solventis in the range from about 75.0 wt % to about 99.9 wt %.

In certain embodiments of the medicament delivery device, the liquidformulation composition further includes an active pharmaceuticalingredient, wherein the active pharmaceutical ingredient is selectedfrom one of medicines for treating rhinitis, sinusitis, lowerrespiratory tract inflammation, otitis media, otitis externa,xerostomia, xerophthalmia, xeromycteria, or a combination thereof.

Any suitable active pharmaceutical ingredients may be utilized. Forexample, active pharmaceutical ingredient of the liquid formulationcomposition may include one of cortisone, hydrocortisone,beclomethasone, triamcinolone acetonide, mometasone, dexamethasone,fluocinolone acetonide, budesonide, fluticasone, ephedrinehydrochloride, xylometazoline hydrochloride, levocabastinehydrochloride, azelastine hydrochloride, fructus xanthii, dandelion,radix scutellariae, bitter gourd, herba ephedrae, flos magnoliae, herbaasari, radix angelicae dahuricae, rhizome acori tatarinowii, catechu,Longjing tea, cortex phellodendri, ofloxacin, levofloxacin, norfloxacin,lomefloxacin, tosufloxacin, sparfloxacin, roxithromycin, chloromycetin,penicillin, clindamycin, nitrofurazone, amoxicillin, ampicillin,clavulanate potassium, cefaclor, cefixime, cefdinir, cephradine,cephalexin, cefpodoxime, cefuroxime axetil, cefprozil, azithromycin,minocycline, acetyl midecamycin, acetylspiramycin, metronidazole, musk,potassium aluminium sulfate anhydrous, calamine, borneol, cochineal,cacumen platycladi, echinacea root, baptisia tinctoria root,D-panthenol, glycerin, hyaluronic acid, butanediol, polyethylene glycol,propanediol, hexanediol, xylitol, sorbitol, or a combination thereof.

In certain embodiments of the medicament delivery device, in the liquidformulation composition, the content of the surfactant is in the rangefrom about 0.1 wt % to about 25.0 wt %, the content of the solvent is inthe range from about 70.0 wt % to about 99.899 wt %, and the content ofthe active pharmaceutical ingredient is in the range from about 0.001 wt% to about 5.0 wt %.

In certain embodiments of the medicament delivery device, the liquidformulation composition further includes one of bacteriostatic agent,flavoring agent, stabilizer, antioxidant, or a combination thereof.

In certain embodiments of the medicament delivery device, thebacteriostatic agent includes one of parabens or its salts, benzoic acidor its salts, benzyl alcohol, phenylethanol, phenylacetic acid,phenoxyethanol, lauric acid monoglyceride, chlorobutanol, sorbic acid orits salts, calcium propionate, sodium propionate, dehydroacetic acid orits salts, sodium diacetate, benzalkonium chloride, benzalkoniumbromide, cetrimide, chlorhexidine acetate, propanediol, carbon dioxide,nisin, natamycin, momordicin, thimerosal, mercuric nitrate, or acombination thereof.

In certain embodiments of the medicament delivery device, the flavoringagent includes one of menthol, borneol, lemon oil, patchouli oil,cinnamon oil, jujube tincture, vanillin, peppermint oil, rose oil,eucalyptus oil, spearmint oil, eugenol, citral, jasmine extract,chrysanthemum extract, osmanthus extract, benzyl alcohol, phenylethanol,terpineol, methyl cyclopentenolone, α-amyl cinnamic aldehyde, butyricacid, hexanoic acid, isoamyl acetate, benzyl acetate, linalyl acetate,ethyl propionate, ethyl butyrate, isoamyl butyrate, benzyl butyrate,isoamyl isovalerate, ethyl hexanoate, ethyl heptanoate, ethyl lactate,allyl hexanoate, γ-nonalactone, ethyl maltol, allyl cyclohexylpropionate, maltol, γ-undecalactone, raspberry ketone, benzylpropionate, butyl butyrate, ethyl isovalerate, ethyl formate, benzylbenzoate, methyl pyrazine, 2,3-dimethyl pyrazine, trimethyl pyrazine,2-acetyl pyrazine, 4-methyl-5-(β-hydroxyethyl) thiazole, 2-acetylthiazole, 2,3,5,6-tetramethyl pyrazine, hexadecanal, ethyl vanillin,hydroxyl citronellal, or a combination thereof.

In certain embodiments of the medicament delivery device, the stabilizerincludes one of lecithin, poloxamer, saponin, tannin, glycerin fattyacid ester, sucrose fatty acid ester, propanediol fatty acid ester,cholesterol, cholesterol ester, polyethylene glycol, cellulose or itsderivatives, dextrin, Arabic gum, tragacanth gum, pectin cellulosecheese, gelatin, alginic acid, or a combination thereof.

In certain embodiments of the medicament delivery device, theantioxidant includes one of tert-butyl hydroxy anisole, butylatedhydroxytoluene, tert-butyl hydroquinone, propyl gallate, ascorbylpalmitate, dilauryl thiodipropionate, 4-hexyl resorcinol, tocopherol,L-ascorbic acid, D-sodium erythorbate, tea polyphenols, rosemaryextract, ginger extract, sugar alcohols, amino acids, or a combinationthereof.

In certain embodiments of the medicament delivery device, in the liquidformulation composition, the content of the surfactant is in the rangefrom about 0.1 wt % to about 25.0 wt %, the content of the solvent is inthe range from about 58.0 wt % to about 99.878 wt %, the content of thebacteriostatic agent is in the range from about 0.001 wt % to about 2.0wt %, the content of the flavoring agent is in the range from about 0.01wt % to about 5.0 wt %, the content of the stabilizer is in the rangefrom about 0.01 wt % to about 5.0 wt %, and the content of theantioxidant is in the range from about 0.001 wt % to 5.0 wt %. Incertain embodiments of the medicament delivery device, the content ofthe active pharmaceutical ingredient is in the range from about 0.001 wt% to about 5.0 wt %.

In yet another aspect, the invention generally relates to a method forpreparing a liquid formulation composition. The method includes: (S1)dissolving or dispersing a surfactant in a solvent to form a solution ora stable suspension; and (S2) adjusting the solution or a stablesuspension to form a liquid formulation composition characterized by asurface tension of less than about 60 mN/m and a pH value from about 5.0to about 7.4.

In certain embodiments of the method, the surfactant includes one ofnatural phospholipid, sterol, pulmonary surfactant, stearic acid, oleicacid, lauric acid, benzalkonium chloride, benzalkonium bromide,cetrimide, sorbitan fatty acid, polysorbate, polyoxyethylene stearate,polyoxyethylene-fatty alcohol ether, poloxamer, dipalmitoylphosphatidylcholine, cholesterol, cholesteryl ester, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, polyethyleneglycol, or a combination thereof.

In certain embodiments of the method, the surfactant includes one oflecithin, sterol, pulmonary surfactant, poloxamer, dipalmitoylphosphatidylcholine, cholesterol, cholesteryl ester, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, polyethyleneglycol, or a combination thereof; and the solvent thereof is one ofwater, ethanol, glycerol, medical silicone oil, edible vegetable oil, ora combination thereof.

In certain embodiments of the method, in the liquid formulationcomposition, the content of the surfactant is in the range from about0.0001 wt % to about 25.0 wt %, and the content of the solvent is in therange from about 75.0 wt % to about 99.9999 wt %.

In certain embodiments of the method, in step (S2), an activepharmaceutical ingredient is uniformly mixed with the surfactant and thesolvent, wherein the active pharmaceutical ingredient includes one ofmedicines for treating rhinitis, sinusitis, lower respiratory tractinflammation, otitis media, otitis externa, xerostomia, xerophthalmia,xeromycteria, or a combination thereof.

Any suitable active pharmaceutical ingredients may be utilized, forexample, one of cortisone, hydrocortisone, beclomethasone, triamcinoloneacetonide, mometasone, dexamethasone, fluocinolone acetonide,budesonide, fluticasone, ephedrine hydrochloride, xylometazolinehydrochloride, levocabastine hydrochloride, azelastine hydrochloride,fructus xanthii, dandelion, radix scutellariae, bitter gourd, herbaephedrae, flos magnoliae, herba asari, radix angelicae dahuricae,rhizome acori tatarinowii, catechu, Longjing tea, cortex phellodendroni,ofloxacin, levofloxacin, norfloxacin, lomefloxacin, tosufloxacin,sparfloxacin, roxithromycin, chloromycetin, penicillin, clindamycin,nitrofurazone, amoxicillin, ampicillin, clavulanate potassium, cefaclor,cefixime, cefdinir, cephradine, cephalexin, cefpodoxime, cefuroximeaxetil, cefprozil, azithromycin, minocycline, acetyl midecamycin,acetylspiramycin, metronidazole, musk, potassium aluminium sulfateanhydrous, calamine, borneol, cochineal, cacumen platycladi, echinacearoot, baptisia tinctoria root, D-panthenol, glycerin, hyaluronic acid,butanediol, polyethylene glycol, propanediol, hexanediol, xylitol,sorbitol, or a combination thereof.

In certain embodiments of the method, in the liquid formulationcomposition, the content of the surfactant is in the range from about0.0001 wt % to about 25.0 wt %, the content of the solvent is in therange from about 70.0 wt % to about 99.9989 wt %, and the content of theactive pharmaceutical ingredient is in the range from about 0.001 wt %to about 5.0 wt %.

In certain embodiments, the method further includes the step ofdissolving or dispersing one of bacteriostatic agent, flavoring agent,stabilizer, antioxidant, or a combination thereof in the solvent.

In certain embodiments of the method, in the liquid formulationcomposition, the content of the surfactant is in the range from about0.0001 wt % to about 25.0 wt %, the content of the solvent is in therange from about 63.0 wt % to about 99.9879 wt %, the content of thebacteriostatic agent is in the range from about 0.001 wt % to about 2.0wt %, the content of the flavoring agent is in the range from about 0.01wt % to about 5.0 wt %, and the content of the antioxidant is in therange from about 0.001 wt % to about 5.0 wt %. In certain embodiments,the content of the surfactant is in the range from about 0.0001 wt % toabout 25.0 wt %, the content of the solvent is in the range from about58.0 wt % to about 99.9869 wt %, the content of the bacteriostatic agentis in the range from about 0.001 wt % to about 2.0 wt %, the content ofthe flavoring agent is in the range from about 0.01 wt % to about 5.0 wt%, and the content of the antioxidant is in the range from about 0.001wt % to about 5.0 wt %, the content of the pharmaceutical ingredient inthe range from about 0.001 wt % to about 5.0 wt %.

In certain embodiments of the method, the bacteriostatic agent includesone of parabens or its salts, benzoic acid or its salts, benzyl alcohol,phenylethanol, phenylacetic acid, phenoxyethanol, lauric acidmonoglyceride, chlorobutanol, sorbic acid or its salts, calciumpropionate, sodium propionate, dehydroacetic acid or its salts thereof,sodium diacetate, benzalkonium chloride, benzalkonium bromide,cetrimide, chlorhexidine acetate, propanediol, carbon dioxide, nisin,natamycin, momordicin, thimerosal, mercuric nitrate, or a combinationthereof.

In certain embodiments of the method, the flavoring agent includes oneof menthol, borneol, lemon oil, patchouli oil, cinnamon oil, jujubetincture, vanillin, peppermint oil, rose oil, eucalyptus oil, spearmintoil, eugenol, citral, jasmine extract, chrysanthemum extract, osmanthusextract, benzyl alcohol, phenylethanol, terpineol, methylcyclopentenolone, α-amyl cinnamic aldehyde, butyric acid, hexanoic acid,isoamyl acetate, benzyl acetate, linalyl acetate, ethyl propionate,ethyl butyrate, isoamyl butyrate, benzyl butyrate, isoamyl isovalerate,ethyl hexanoate, ethyl heptanoate, ethyl lactate, allyl hexanoate,γ-nonalactone, ethyl maltol, allyl cyclohexyl propionate, maltol,γ-undecalactone, raspberry ketone, benzyl propionate, butyl butyrate,ethyl isovalerate, ethyl formate, benzyl benzoate, methyl pyrazine,2,3-dimethyl pyrazine, trimethyl pyrazine, 2-acetyl pyrazine,4-methyl-5-(β-hydroxyethyl) thiazole, 2-acetyl thiazole,2,3,5,6-tetramethyl pyrazine, hexadecanal, ethyl vanillin, hydroxylcitronellal, or a combination thereof.

In certain embodiments of the method, the stabilizer includes one oflecithin, poloxamer, saponin, tannin, glycerin fatty acid ester, sucrosefatty acid ester, propanediol fatty acid ester, cholesterol, cholesterolester, polyethylene glycol, cellulose or its derivatives, dextrin,Arabic gum, tragacanth gum, pectin cellulose cheese, gelatin, alginicacid, or a combination thereof.

In certain embodiments of the method, the antioxidant includes one oftert-butyl hydroxy anisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, ascorbyl palmitate, dilaurylthiodipropionate, 4-hexyl resorcinol, tocopherol (vitamin E), L-ascorbicacid, D-sodium erythorbate, tea polyphenols, rosemary extract, gingerextract, sugar alcohols, amino acids, or a combination thereof.

In yet another aspect, the invention generally relates to a method forpreparing a liquid formulation composition. The method includes: (S1)dissolving or dispersing a surfactant in a solvent with an ultrasound ofabout 40 KHz to about 60 KHz for about 1 minute to about 3 minutes; and(S2) uniformly mixing an active pharmaceutical ingredient, thesurfactant and a solvent under a stirring condition characterized by arotational speed of more than 3000 rpm to form a liquid formulationcomposition characterized by a surface tension of less than about 60mN/m and an absolute value of zeta potential of greater than about 15mV.

In certain embodiments, the method further includes, after step (S2),ultrasonically crushing or high-pressure homogenizing the liquidformulation composition so as to form liquid particles with the volumeaverage particle size in the range from about 50 nm to about 500 nm.

In certain embodiments of the method, in the liquid formulationcomposition, the content of the surfactant is in the range from about0.1 wt % to about 25.0 wt %, and the content of the solvent is in therange from about 75.0 wt % to about 99.9 wt %.

In certain embodiments, the method further includes the step ofdispersing one of bacteriostatic agent, flavoring agent, stabilizer,antioxidant, or a combination thereof in the solvent. In the liquidformulation composition, the content of the surfactant is in the rangefrom about 0.1 wt % to about 25.0 wt %, the content of the solvent is inthe range from about 58.0 wt % to about 99.878 wt %, the content of thebacteriostatic agent is in the range from about 0.001 wt % to about 2.0wt %, the content of the flavoring agent is in the range from about 0.01wt % to about 5.0 wt %, the content of the stabilizer is in the rangefrom about 0.01 wt % to about 5.0 wt %, and the content of theantioxidant is in the range from about 0.001 wt % to about 5.0 wt %.

In certain embodiments of the method, the bacteriostatic agent includesone of parabens or its salts, benzoic acid or its salts, benzyl alcohol,phenylethanol, phenylacetic acid, phenoxyethanol, lauric acidmonoglyceride, chlorobutanol, sorbic acid or its salts, calciumpropionate, sodium propionate, dehydroacetic acid or its salts, sodiumdiacetate, benzalkonium chloride, benzalkonium bromide, cetrimide,chlorhexidine acetate, propanediol, carbon dioxide, nisin, natamycin,momordicin, thimerosal, mercuric nitrate, or a combination thereof.

In certain embodiments of the method, the flavoring agent thereofincludes one of menthol, borneol, lemon oil, patchouli oil, cinnamonoil, jujube tincture, vanillin, peppermint oil, rose oil, eucalyptusoil, spearmint oil, eugenol, citral, jasmine extract, chrysanthemumextract, osmanthus extract, benzyl alcohol, phenylethanol, terpineol,methyl cyclopentenolone, α-amyl cinnamic aldehyde, butyric acid,hexanoic acid, isoamyl acetate, benzyl acetate, linalyl acetate, ethylpropionate, ethyl butyrate, isoamyl butyrate, benzyl butyrate, isoamylisovalerate, ethyl hexanoate, ethyl heptanoate, ethyl lactate, allylhexanoate, γ-nonalactone, ethyl maltol, allyl cyclohexyl propionate,maltol, γ-undecalactone, raspberry ketone, benzyl propionate, butylbutyrate, ethyl isovalerate, ethyl formate, benzyl benzoate, methylpyrazine, 2,3-dimethyl pyrazine, trimethyl pyrazine, 2-acetyl pyrazine,4-methyl-5-(β-hydroxyethyl) thiazole, 2-acetyl thiazole,2,3,5,6-tetramethyl pyrazine, hexadecanal, ethyl vanillin, hydroxylcitronellal, or a combination thereof.

In certain embodiments of the method, the stabilizer includes one oflecithin, poloxamer, saponin, tannin, glycerin fatty acid ester, sucrosefatty acid ester, propanediol fatty acid ester, cholesterol, cholesterolester, polyethylene glycol, cellulose or its derivatives, dextrin,Arabic gum, tragacanth gum, pectin cellulose cheese, gelatin, alginicacid, or a combination thereof.

In certain embodiments of the method, the antioxidant includes one oftert-butyl hydroxy anisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, ascorbyl palmitate, dilaurylthiodipropionate, 4-hexyl resorcinol, tocopherol, L-ascorbic acid,D-sodium erythorbate, tea polyphenols, rosemary extract, ginger extract,sugar alcohols, amino acids, or a combination thereof.

Any suitable surfactant(s) may be utilized. In certain embodiments ofthe method, the surfactant includes one of natural phospholipid, sterol,pulmonary surfactant, stearic acid, oleic acid, lauric acid,benzalkonium chloride, benzalkonium bromide, cetrimide, sorbitan fattyacid, polysorbate, polyoxyethylene stearate, polyoxyethylene-fattyalcohol ether, poloxamer, dipalmitoyl phosphatidylcholine, cholesterol,cholesteryl ester, phosphatidyl ethanolamine, phosphatidylglycerol,phosphatidylserine, polyethylene glycol, or a combination thereof.

In certain embodiments of the method, the surfactant includes one oflecithin, sterol, pulmonary surfactant, poloxamer, dipalmitoylphosphatidylcholine, cholesterol, cholesteryl ester, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, polyethyleneglycol, or a combination thereof.

In certain embodiments, the invention provides a solid formulationcomposition obtained by removing the solvent from the liquid formulationcomposition of the invention.

In yet another aspect, the invention generally relates to a method forpreparing the liquid formulation composition. The method includes: (S1)dissolving or dispersing a surfactant in a solvent with an ultrasound ofabout 40 KHz to about 60 KHz for about 1 minute to about 3 minutes; and(S2) uniformly mixing an active pharmaceutical ingredient, thesurfactant and a solvent under a stirring condition characterized by arotational speed of more than 3000 rpm to form a liquid formulationcomposition in the form of an emulsion. The liquid formulationcomposition includes a solvent and, dispersed therein, liquid particlesincluding a surfactant. The volume average particle size of the liquidparticles is less than about 100 μm. The liquid formulation compositionis characterized by a surface tension of less than about 60 mN/m and anabsolute value of zeta potential of more than about 15 mV. The activepharmaceutical ingredient is selected from one of medicines for treatingrhinitis, sinusitis, lower respiratory tract inflammation, otitis media,otitis externa, xerostomia, xerophthalmia, xeromycteria, or acombination thereof.

In certain embodiments, the method further includes, after step (S2),ultrasonically crushing or high-pressure homogenizing the liquidformulation composition so as to form liquid particles with the volumeaverage particle size in the range from about 50 to about 500 nm.

In certain embodiments of the method, the surfactant is in the rangefrom about 0.1 wt % to about 25.0 wt %; the solvent is in the range fromabout 70.0 wt % to about 99.899 wt %; and the active pharmaceuticalingredient is in the range from about 0.001 wt % to about 5.0 wt %.

In certain embodiments, the method further includes, the step ofdispersing one of bacteriostatic agent, flavoring agent, stabilizer,antioxidant, or a combination thereof in the solvent, wherein in theliquid formulation composition, the surfactant is in the range fromabout 0.1 wt % to about 25.0 wt %, the solvent is in the range fromabout 53.0 wt % to about 99.878 wt %, the bacteriostatic agent is in therange from about 0.001 wt % to about 2.0 wt %, the flavoring agent is inthe range from about 0.01 wt % to about 5.0 wt %, the adding amount ofthe stabilizer is in the range from about 0.01 wt % to about 5.0 wt %,the antioxidant is in the range from about 0.001 wt % to about 5.0 wt %,and the active pharmaceutical ingredient is in the range from about0.001 wt % to about 5.0 wt %.

In certain embodiments of the method, the bacteriostatic agent includesone of parabens or its salts, benzoic acid or its salts, benzyl alcohol,phenylethanol, phenylacetic acid, phenoxyethanol, lauric acidmonoglyceride, chlorobutanol, sorbic acid or its salts, calciumpropionate, sodium propionate, dehydroacetic acid or its salts thereof,sodium diacetate, benzalkonium chloride, benzalkonium bromide,cetrimide, chlorhexidine acetate, propanediol, carbon dioxide, nisin,natamycin, momordicin, thimerosal, mercuric nitrate, or a combinationthereof.

In certain embodiments of the method, the flavoring agent includes oneof menthol, borneol, lemon oil, patchouli oil, cinnamon oil, jujubetincture, vanillin, peppermint oil, rose oil, eucalyptus oil, spearmintoil, eugenol, citral, jasmine extract, chrysanthemum extract, osmanthusextract, benzyl alcohol, phenylethanol, terpineol, methylcyclopentenolone, α-amyl cinnamic aldehyde, butyric acid, hexanoic acid,isoamyl acetate, benzyl acetate, linalyl acetate, ethyl propionate,ethyl butyrate, isoamyl butyrate, benzyl butyrate, isoamyl isovalerate,ethyl hexanoate, ethyl heptanoate, ethyl lactate, allyl hexanoate,γ-nonalactone, ethyl maltol, allyl cyclohexyl propionate, maltol,γ-undecalactone, raspberry ketone, benzyl propionate, butyl butyrate,ethyl isovalerate, ethyl formate, benzyl benzoate, methyl pyrazine,2,3-dimethyl pyrazine, trimethyl pyrazine, 2-acetyl pyrazine,4-methyl-5-(β-hydroxyethyl) thiazole, 2-acetyl thiazole,2,3,5,6-tetramethyl pyrazine, hexadecanal, ethyl vanillin, hydroxylcitronellal, or a combination thereof.

In certain embodiments of the method, the stabilizer includes one oflecithin, poloxamer, saponin, tannin, glycerin fatty acid ester, sucrosefatty acid ester, propanediol fatty acid ester, cholesterol, cholesterolester, polyethylene glycol, cellulose or its derivatives, dextrin,Arabic gum, tragacanth gum, pectin cellulose cheese, gelatin, alginicacid, or a combination thereof; and

In certain embodiments of the method, the antioxidant includes one oftert-butyl hydroxy anisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, ascorbyl palmitate, dilaurylthiodipropionate, 4-hexyl resorcinol, tocopherol (vitamin E), L-ascorbicacid, D-sodium erythorbate, tea polyphenols, rosemary extract, gingerextract, sugar alcohols, amino acids, or a combination thereof.

In certain embodiments of the method, the surfactant includes one ofnatural phospholipid, sterol, pulmonary surfactant, stearic acid, oleicacid, lauric acid, benzalkonium chloride, benzalkonium bromide,cetrimide, sorbitan fatty acid, polysorbate, polyoxyethylene stearate,polyoxyethylene-fatty alcohol ether, poloxamer, dipalmitoylphosphatidylcholine, cholesterol, cholesteryl ester, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, polyethyleneglycol, or a combination thereof the solvent is one of water, ethanol,glycerol, medical silicone oil and edible vegetable oil, or acombination thereof and the active pharmaceutical ingredient includesone of cortisone, hydrocortisone, beclomethasone, triamcinoloneacetonide, mometasone, dexamethasone, fluocinolone acetonide,budesonide, fluticasone, ephedrine hydrochloride, xylometazolinehydrochloride, levocabastine hydrochloride, azelastine hydrochloride,fructus xanthii, dandelion, radix scutellariae, bitter gourd, herbaephedrae, flos magnoliae, herba asari, radix angelicae dahuricae,rhizome acori tatarinowii, catechu, Longjing tea, cortex phellodendri,ofloxacin, levofloxacin, norfloxacin, lomefloxacin, tosufloxacin,sparfloxacin, roxithromycin, chloromycetin, penicillin, clindamycin,nitrofurazone, amoxicillin, ampicillin, clavulanate potassium, cefaclor,cefixime, cefdinir, cephradine, cephalexin, cefpodoxime, cefuroximeaxetil, cefprozil, azithromycin, minocycline, acetyl midecamycin,acetylspiramycin, metronidazole, musk, potassium aluminium sulfateanhydrous, calamine, borneol, cochineal, cacumen platycladi, echinacearoot, baptisia tinctoria root, D-panthenol, glycerin, hyaluronic acid,butanediol, polyethylene glycol, propanediol, hexanediol, xylitol,sorbitol, or a combination thereof.

In yet another aspect, the invention generally relates to a method forpreparing a medicament delivery device. The method includes: (S1)dissolving or dispersing a surfactant in a solvent to form a solution ora stable suspension; and (S2) adjusting the solution to form a liquidformulation composition characterized by a surface tension of less thanabout 60 mN/m and a pH value from about 5.0 to about 7.4, and (S3)filling the liquid formulation composition into a containment vessel.

In certain embodiments of the method, the containment vessel isconfigured to function as a sprayer, allowing controlled spraying of theliquid formulation composition out of the outlet.

In certain embodiments of the method, the containment vessel isconfigured to function as a dropping device, allowing controlleddropping of the liquid formulation composition out of the outlet.

In certain embodiments of the method, the buffer is added to keep the pHvalue of solution in the range of about 5.0 to about 7.4.

In certain embodiments of the method, the surfactant includes one ofnatural phospholipid, sterol, pulmonary surfactant, stearic acid, oleicacid, lauric acid, benzalkonium chloride, benzalkonium bromide,cetrimide, sorbitan fatty acid, polysorbate, polyoxyethylene stearate,polyoxyethylene-fatty alcohol ether, poloxamer, dipalmitoylphosphatidylcholine, cholesterol, cholesteryl ester, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, polyethyleneglycol, or a combination thereof.

In certain embodiments of the method, the surfactant includes one oflecithin, sterol, pulmonary surfactant, poloxamer, dipalmitoylphosphatidylcholine, cholesterol, cholesteryl ester, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, polyethyleneglycol, or a combination thereof; and the solvent thereof is one ofwater, ethanol, glycerol, medical silicone oil, edible vegetable oil, ora combination thereof.

In certain embodiments of the method, in the liquid formulationcomposition, the content of the surfactant is in the range from about0.0001 wt % to about 25.0 wt %, and the content of the solvent is in therange from about 75.0 wt % to about 99.9999 wt %.

In certain embodiments of the method, in step (S2), an activepharmaceutical ingredient is uniformly mixed with the surfactant and thesolvent, wherein the active pharmaceutical ingredient includes one ofmedicines for treating rhinitis, sinusitis, lower respiratory tractinflammation, otitis media, otitis externa, xerostomia, xerophthalmia,xeromycteria, or a combination thereof.

Any suitable active pharmaceutical ingredients may be utilized, forexample, one of cortisone, hydrocortisone, beclomethasone, triamcinoloneacetonide, mometasone, dexamethasone, fluocinolone acetonide,budesonide, fluticasone, ephedrine hydrochloride, xylometazolinehydrochloride, levocabastine hydrochloride, azelastine hydrochloride,fructus xanthii, dandelion, radix scutellariae, bitter gourd, herbaephedrae, flos magnoliae, herba asari, radix angelicae dahuricae,rhizome acori tatarinowii, catechu, Longjing tea, cortex phellodendroni,ofloxacin, levofloxacin, norfloxacin, lomefloxacin, tosufloxacin,sparfloxacin, roxithromycin, chloromycetin, penicillin, clindamycin,nitrofurazone, amoxicillin, ampicillin, clavulanate potassium, cefaclor,cefixime, cefdinir, cephradine, cephalexin, cefpodoxime, cefuroximeaxetil, cefprozil, azithromycin, minocycline, acetyl midecamycin,acetylspiramycin, metronidazole, musk, potassium aluminium sulfateanhydrous, calamine, borneol, cochineal, cacumen platycladi, echinacearoot, baptisia tinctoria root, D-panthenol, glycerin, hyaluronic acid,butanediol, polyethylene glycol, propanediol, hexanediol, xylitol,sorbitol, or a combination thereof.

In certain embodiments of the method, in the liquid formulationcomposition, the content of the surfactant is in the range from about0.0001 wt % to about 25.0 wt %, the content of the solvent is in therange from about 70.0 wt % to about 99.9989 wt %, and the content of theactive pharmaceutical ingredient is in the range from about 0.001 wt %to about 5.0 wt %.

In certain embodiments, the method further includes the step ofdispersing one of bacteriostatic agent, flavoring agent, stabilizer,antioxidant, or a combination thereof in the solvent.

In certain embodiments of the method, in the liquid formulationcomposition, the content of the surfactant is in the range from about0.0001 wt % to about 25.0 wt %, the content of the solvent is in therange from about 58.0 wt % to about 99.9689 wt %, the content of thebacteriostatic agent is in the range from about 0.001 wt % to about 2.0wt %, the content of the flavoring agent is in the range from about 0.01wt % to about 5.0 wt %, and the content of the antioxidant is in therange from about 0.001 wt % to about 5.0 wt %. In certain embodiments,the content of the pharmaceutical ingredient in the range from about0.001 wt % to about 5.0 wt %.

In certain embodiments of the method, the bacteriostatic agent includesone of parabens or its salts, benzoic acid or its salts, benzyl alcohol,phenylethanol, phenylacetic acid, phenoxyethanol, lauric acidmonoglyceride, chlorobutanol, sorbic acid or its salts, calciumpropionate, sodium propionate, dehydroacetic acid or its salts thereof,sodium diacetate, benzalkonium chloride, benzalkonium bromide,cetrimide, chlorhexidine acetate, propanediol, carbon dioxide, nisin,natamycin, momordicin, thimerosal, mercuric nitrate, or a combinationthereof.

In certain embodiments of the method, the flavoring agent includes oneof menthol, borneol, lemon oil, patchouli oil, cinnamon oil, jujubetincture, vanillin, peppermint oil, rose oil, eucalyptus oil, spearmintoil, eugenol, citral, jasmine extract, chrysanthemum extract, osmanthusextract, benzyl alcohol, phenylethanol, terpineol, methylcyclopentenolone, α-amyl cinnamic aldehyde, butyric acid, hexanoic acid,isoamyl acetate, benzyl acetate, linalyl acetate, ethyl propionate,ethyl butyrate, isoamyl butyrate, benzyl butyrate, isoamyl isovalerate,ethyl hexanoate, ethyl heptanoate, ethyl lactate, allyl hexanoate,γ-nonalactone, ethyl maltol, allyl cyclohexyl propionate, maltol,γ-undecalactone, raspberry ketone, benzyl propionate, butyl butyrate,ethyl isovalerate, ethyl formate, benzyl benzoate, methyl pyrazine,2,3-dimethyl pyrazine, trimethyl pyrazine, 2-acetyl pyrazine,4-methyl-5-(β-hydroxyethyl) thiazole, 2-acetyl thiazole,2,3,5,6-tetramethyl pyrazine, hexadecanal, ethyl vanillin, hydroxylcitronellal, or a combination thereof.

In certain embodiments of the method, the stabilizer includes one oflecithin, poloxamer, saponin, tannin, glycerin fatty acid ester, sucrosefatty acid ester, propanediol fatty acid ester, cholesterol, cholesterolester, polyethylene glycol, cellulose or its derivatives, dextrin,Arabic gum, tragacanth gum, pectin cellulose cheese, gelatin, alginicacid, or a combination thereof.

In certain embodiments of the method, the antioxidant includes one oftert-butyl hydroxy anisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, ascorbyl palmitate, dilaurylthiodipropionate, 4-hexyl resorcinol, tocopherol (vitamin E), L-ascorbicacid, D-sodium erythorbate, tea polyphenols, rosemary extract, gingerextract, sugar alcohols, amino acids, or a combination thereof.

In yet another aspect, the invention generally relates to a method forpreparing the medicament delivery device. The method include: (S1)dissolving or dispersing a surfactant in a solvent with an ultrasound ofabout 40 KHz to about 60 KHz for about 1 minute to about 3 minutes; and(S2) uniformly mixing the surfactant with a solvent under a stirringcondition characterized by a rotational speed of more than 3000 rpm toform a liquid formulation. The liquid formulation composition is anemulsion and includes a solvent and, dispersed therein, liquid particlesincluding a surfactant. The volume average particle size of the liquidparticles is less than about 100 μm. The liquid formulation compositionis characterized by a surface tension of less than about 60 mN/m and anabsolute value of zeta potential of more than about 15 mV; and (S3)filling the liquid formulation composition into a containment vessel.

In certain embodiments of the method, the containment vessel isconfigured to function as a sprayer, allowing controlled spraying of theliquid formulation composition out of the outlet.

In certain embodiments of the method, the containment vessel isconfigured to function as a dropping device, allowing controlleddropping of the liquid formulation composition out of the outlet.

In certain embodiments, the method further includes, after step (S2),ultrasonically crushing or high-pressure homogenizing the liquidformulation composition so as to form liquid particles with the volumeaverage particle size in the range from about 50 nm to about 500 nm.

In certain embodiments of the method, the surfactant includes one ofnatural phospholipid, sterol, pulmonary surfactant, stearic acid, oleicacid, lauric acid, benzalkonium chloride, benzalkonium bromide,cetrimide, sorbitan fatty acid, polysorbate, polyoxyethylene stearate,polyoxyethylene-fatty alcohol ether, poloxamer, dipalmitoylphosphatidylcholine, cholesterol, cholesteryl ester, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, polyethyleneglycol, or a combination thereof.

In certain embodiments of the method, the surfactant includes one oflecithin, sterol, pulmonary surfactant, poloxamer, dipalmitoylphosphatidylcholine, cholesterol, cholesteryl ester, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, polyethyleneglycol, or a combination thereof; and the solvent thereof is one ofwater, ethanol, glycerol, medical silicone oil, edible vegetable oil, ora combination thereof.

In certain embodiments of the method, in the liquid formulationcomposition, the content of the surfactant is in the range from about0.1 wt % to about 25.0 wt %, and the content of the solvent is in therange from about 75.0 wt % to about 99.9 wt %.

In certain embodiments, the method further includes the step ofdispersing one of bacteriostatic agent, flavoring agent, stabilizer,antioxidant, or a combination thereof in the solvent.

In certain embodiments of the method, in the liquid formulationcomposition, the content of the surfactant is in the range from about0.1 wt % to about 25.0 wt %, the content of the solvent is in the rangefrom about 58.0 wt % to about 99.878 wt %, the content of thebacteriostatic agent is in the range from about 0.001 wt % to about 2.0wt %, the content of the flavoring agent is in the range from about 0.01wt % to about 5.0 wt %, the content of the stabilizer is in the rangefrom about 0.01 wt % to about 5.0 wt %, and the content of theantioxidant is in the range from about 0.001 wt % to about 5.0 wt %.

In certain embodiments of the method, the bacteriostatic agent includesone of parabens or its salts, benzoic acid or its salts, benzyl alcohol,phenylethanol, phenylacetic acid, phenoxyethanol, lauric acidmonoglyceride, chlorobutanol, sorbic acid or its salts, calciumpropionate, sodium propionate, dehydroacetic acid or its salts thereof,sodium diacetate, benzalkonium chloride, benzalkonium bromide,cetrimide, chlorhexidine acetate, propanediol, carbon dioxide, nisin,natamycin, momordicin, thimerosal, mercuric nitrate, or a combinationthereof.

In certain embodiments of the method, the flavoring agent includes oneof menthol, borneol, lemon oil, patchouli oil, cinnamon oil, jujubetincture, vanillin, peppermint oil, rose oil, eucalyptus oil, spearmintoil, eugenol, citral, jasmine extract, chrysanthemum extract, osmanthusextract, benzyl alcohol, phenylethanol, terpineol, methylcyclopentenolone, α-amyl cinnamic aldehyde, butyric acid, hexanoic acid,isoamyl acetate, benzyl acetate, linalyl acetate, ethyl propionate,ethyl butyrate, isoamyl butyrate, benzyl butyrate, isoamyl isovalerate,ethyl hexanoate, ethyl heptanoate, ethyl lactate, allyl hexanoate,γ-nonalactone, ethyl maltol, allyl cyclohexyl propionate, maltol,γ-undecalactone, raspberry ketone, benzyl propionate, butyl butyrate,ethyl isovalerate, ethyl formate, benzyl benzoate, methyl pyrazine,2,3-dimethyl pyrazine, trimethyl pyrazine, 2-acetyl pyrazine,4-methyl-5-(β-hydroxyethyl) thiazole, 2-acetyl thiazole,2,3,5,6-tetramethyl pyrazine, hexadecanal, ethyl vanillin, hydroxylcitronellal, or a combination thereof.

In certain embodiments of the method, the stabilizer includes one oflecithin, poloxamer, saponin, tannin, glycerin fatty acid ester, sucrosefatty acid ester, propanediol fatty acid ester, cholesterol, cholesterolester, polyethylene glycol, cellulose or its derivatives, dextrin,Arabic gum, tragacanth gum, pectin cellulose cheese, gelatin, alginicacid, or a combination thereof.

In certain embodiments of the method, the antioxidant includes one oftert-butyl hydroxy anisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, ascorbyl palmitate, dilaurylthiodipropionate, 4-hexyl resorcinol, tocopherol (vitamin E), L-ascorbicacid, D-sodium erythorbate, tea polyphenols, rosemary extract, gingerextract, sugar alcohols, amino acids, or a combination thereof.

In certain embodiments of the method, in step (S2), an activepharmaceutical ingredient is uniformly mixed with the surfactant and thesolvent, wherein the active pharmaceutical ingredient includes one ofmedicines for treating rhinitis, sinusitis, lower respiratory tractinflammation, otitis media, otitis externa, xerostomia, xerophthalmia,xeromycteria, or a combination thereof.

In certain embodiments of the method, the active pharmaceuticalingredient includes one of cortisone, hydrocortisone, beclomethasone,triamcinolone acetonide, mometasone, dexamethasone, fluocinoloneacetonide, budesonide, fluticasone, ephedrine hydrochloride,xylometazoline hydrochloride, levocabastine hydrochloride, azelastinehydrochloride, fructus xanthii, dandelion, radix scutellariae, bittergourd, herba ephedrae, flos magnoliae, herba asari, radix angelicaedahuricae, rhizome acori tatarinowii, catechu, Longjing tea, cortexphellodendroni, ofloxacin, levofloxacin, norfloxacin, lomefloxacin,tosufloxacin, sparfloxacin, roxithromycin, chloromycetin, penicillin,clindamycin, nitrofurazone, amoxicillin, ampicillin, clavulanatepotassium, cefaclor, cefixime, cefdinir, cephradine, cephalexin,cefpodoxime, cefuroxime axetil, cefprozil, azithromycin, minocycline,acetyl midecamycin, acetylspiramycin, metronidazole, musk, potassiumaluminium sulfate anhydrous, calamine, borneol, cochineal, cacumenplatycladi, Echinacea root, baptisia tinctoria root, D-panthenol,glycerin, hyaluronic acid, butanediol, polyethylene glycol, propanediol,hexanediol, xylitol, sorbitol, or a combination thereof.

In certain embodiments of the method, in the liquid formulationcomposition the content of the surfactant is in the range from about 0.1wt % to about 25.0 wt %, the content of the solvent is in the range fromabout 53.0 wt % to about 99.877 wt %, the content of the bacteriostaticagent is in the range from about 0.001 wt % to about 2.0 wt %, thecontent of the flavoring agent is in the range from about 0.01 wt % toabout 5.0 wt %, the content of the stabilizer is in the range from about0.01 wt % to about 5.0 wt %, the content of the antioxidant is in therange from about 0.001 wt % to about 5.0 wt %, and the content of theactive pharmaceutical ingredient is in the range from about 0.001 wt %to about 5.0 wt %.

In certain embodiments of the method, the containment vessel is ananti-contamination sprayer or an anti-contamination dropping device.

In yet another aspect, the invention generally relates to a method fortreating, reducing, or preventing one or more diseases or disorders. Themethod includes administering to a subject in need thereof a liquidformulation composition disclosed herein, in an amount effective totreat, prevent, or reduce one or more diseases or disorders selectedfrom rhinitis, sinusitis, lower respiratory tract inflammation, otitismedia, otitis externa, xerostomia, xerophthalmia and xeromycteria.

In certain embodiments of the method, the one or more diseases ordisorders include otitis media. In certain embodiments of the method,the one or more diseases or disorders include otitis externa. In certainembodiments of the method, the one or more diseases or disorders includerhinitis. In certain embodiments of the method, the one or more diseasesor disorders include sinusitis. In certain embodiments of the method,the one or more diseases or disorders include xerostomia. In certainembodiments of the method, the one or more diseases or disorders includexerophthalmia. In certain embodiments of the method, the one or morediseases or disorders include xeromycteria. In certain embodiments ofthe method, the one or more diseases or disorders include lowerrespiratory tract inflammation.

In yet another aspect, the invention generally relates to a method fortreating, reducing, or preventing one or more diseases or disorders. Themethod includes administering to a subject in need thereof a liquidformulation composition, using the medicament delivery device disclosedherein, in an amount effective to treat, prevent, or reduce one or morediseases or disorders selected from rhinitis, sinusitis, lowerrespiratory tract inflammation, otitis media, otitis externa,xerostomia, xerophthalmia and xeromycteria.

In certain embodiments of the method, the one or more diseases ordisorders include otitis media. In certain embodiments of the method,the one or more diseases or disorders include otitis externa. In certainembodiments of the method, the one or more diseases or disorders includerhinitis. In certain embodiments of the method, the one or more diseasesor disorders include sinusitis. In certain embodiments of the method,the one or more diseases or disorders include xerostomia. In certainembodiments of the method, the one or more diseases or disorders includexerophthalmia. In certain embodiments of the method, the one or morediseases or disorders include xeromycteria. In certain embodiments ofthe method, the one or more diseases or disorders include lowerrespiratory tract inflammation.

In yet another aspect, the invention generally relates to a method fortreatment of otitis media using the liquid formulation composition ofthe invention.

In yet another aspect, the invention generally relates to a method fortreatment of otitis externa using the liquid formulation composition ofthe invention.

In yet another aspect, the invention generally relates to a method fortreatment of rhinitis using the liquid formulation composition of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of sinusitis using the liquid formulation composition of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of xerostomia using the liquid formulation composition of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of xerophthalmia using the liquid formulation composition ofthe invention.

In yet another aspect, the invention generally relates to a method fortreatment of xeromycteria using the liquid formulation composition ofthe invention.

In yet another aspect, the invention generally relates to a method fortreatment of lower respiratory tract inflammation using the liquidformulation composition of the invention.

In yet another aspect, the invention generally relates to a method fortreatment of otitis media using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of otitis externa using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of rhinitis using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of sinusitis using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of xerostomia using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of xerophthalmia using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of xeromycteria using the medicament delivery device of theinvention.

In yet another aspect, the invention generally relates to a method fortreatment of lower respiratory tract inflammation using the medicamentdelivery device of of the invention.

For the liquid formulation compositions disclosed herein, the surfacetension generally should be less than about 60 mN/m. As discussedherein, when the surface tension of the liquid formulation compositionis less than about 60 mN/m, the surface tension Eustachian tube reducedand the surface tension of effusion at mucosa of Eustachian tube is alsoreduced, the effusion can flow out smoothly, the ear pressure can bereduced, and the symptoms of tinnitus and headache can be eliminated;and meanwhile, the risk of infection is reduced, the elimination ofinflammation is promoted, and the healing is promoted.

According to the invention, in order to realize the treatment effect ina faster and better manner, preferably, the surface tension of theliquid formulation composition is less than about 40 mN/m, morepreferably, the surface tension of the liquid formulation composition isless than about 30 mN/m, and most preferably, the surface tension of theliquid formulation composition is less than about 27 mN/m. The smallersurface tension of the liquid formulation composition is more conductiveto reducing the surface tension of the effusion of the Eustachian tubeand more conductive to outflow of the middle ear effusion.

It is noted, however, experiments show that the lesser surface tensionof the liquid formulation composition can make the liquid formulationcomposition less stable, make the surfactant in the solvent easier toaggregate or even stratify or settle, potentially causing poor stabilityand less effective when used in the form of spray or drop.

The volume average particle size is defined as the particle size of ahypothetical particle population that has the same particle shape, thesame total volume and the same number of particles as the particlepopulation, and uniform particle size.

When the particle size of the liquid particles in the solvent meets theabove conditions, the liquid particles can be dispersed in the solventmore stably.

To ensure that the liquid formulation composition disclosed herein hassufficient stability so as to allow the use of a liquid formulationcomposition in the form of spray or drop, the volume average particlesize of the liquid particles is maintained less than about 100 μm, andmore preferably, the volume average particle size of the liquidparticles is less than about 10 μm or even less than about 6 μm.

In certain embodiments, the volume average particle size of the liquidparticles is in the range from about 1 μm to about 100 μm, and morepreferably, the volume average particle size of the liquid particles isin the range from about 1 μm to about 10 μm or even from about 1 μm toabout 6 μm.

In certain embodiments, preferably, the volume average particle size ofthe liquid particles is in the range from about 50 nm to about 500 nm,and more preferably, the volume average particle size of the liquidparticles is in the range from about 100 nm to about 500 nm or even fromabout 200 nm to about 400 nm. At this condition, the stability of theliquid particles in the solvent is increased.

In order to ensure that the liquid formulation composition disclosedherein has sufficient stability, on the premise of ensuring that theparticle size is in the ranges above by the process, the relativecontents of the surfactant, the solvent and other substances which areselectively added in the liquid formulation composition will affect zetapotential, and it is found that, when the absolute value of zetapotential of the liquid formulation composition disclosed herein is morethan 15 mV, the liquid formulation composition has good stability.

As well known to those skilled in the art, the zeta potential which isalso known as electric potential (ζ-potential) refers to potential on ashear plane. More preferably, the absolute value of zeta potential ofthe liquid formulation composition is more than 20 mV or even more than40 mV. At this time, the liquid formulation composition has moredesirable stability.

In certain embodiments of the invention, to improve the stability of theliquid formulation composition and simultaneously reduce the irritationto a user, the pH value of the liquid formulation composition ispreferably in the range from about 5.0 to about 7.4 and more preferablyin the range from about 6.0 to about 7.4.

In the invention, the adopted surfactant can be selected from variousknown and safe substances in the fields of medicines, foods and thelike, for example, the surfactant is selected from, but not limited to,one of natural phospholipid, sterol, pulmonary surfactant, stearic acid,oleic acid, lauric acid, benzalkonium chloride, benzalkonium bromide,cetrimide, sorbitan fatty acid, polysorbate, polyoxyethylene stearate,polyoxyethylene-fatty alcohol ether, poloxamer, dipalmitoylphosphatidylcholine, cholesterol, cholesteryl ester, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, polyethyleneglycol, or a combination thereof. In order to ensure the use safety ofthe liquid formulation composition disclosed herein, the surfactantpreferably adopts substances with high safety and excellent activity,for example, the surfactant is selected from, but not limited to, one oflecithin, sterol, pulmonary surfactant, poloxamer, dipalmitoylphosphatidylcholine, cholesterol, cholesteryl ester, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, polyethyleneglycol, or a combination thereof.

Studies report that in samples of patients with the secretory otitismedia, the content of phospholipid representing a surfactant isobviously reduced in comparison with that of a healthy control group,and the difference has statistical significance (p<0.01), so that thesituation confirms that the reduction of the surfactant in the patientswith the secretory otitis media is mainly shown in the nasopharynx, themiddle ear and part of the eustachian tube, further forces the increaseof the open pressure of the eustachian tube and enables the complianceto be possible, causes the effusion in middle ear cavity and theretention of the effusion, and finally causes the secretory otitismedia. When the above various substances (e.g., phospholipid) are takenas the surfactant, on the basis of realizing the purposes of theinvention, the reduced ingredients (e.g., phospholipid) at nasopharynxesof patients with otitis media and rhinitis can be also supplemented tobring additional symptom reliefs.

For the formulation composition disclosed herein, particularly, when thesurfactant adopts the above various substances, too high or too low pHcan cause hydrolysis of the surfactant, and the stability of theformulation composition can be greatly reduced.

The above various substances are commercially available.

There is no particular limitation of the solvent in the liquidformulation composition disclosed herein, and the solvent can be one ofwater, ethanol, glycerol, medical silicone oil, edible vegetable oil, ora combination thereof. For example, the solvent in the invention iswater.

According to the invention, the relative content of the solvent and thesurfactant in the liquid formulation composition can change within arelatively large range, and as known to those skilled in the art, thedifferent relative contents of the solvent and the surfactant can resultin different surface tension and zeta potential of the liquidformulation composition. In the invention, only the surface tension andthe zeta potential of the liquid formulation composition need to meetthe requirements described above. The liquid formulation composition isprepared by those skilled in the art by adjusting the relative contentsof the solvent and the surfactant to make the surface tension and thezeta potential of the liquid formulation composition within the rangedescribed above. Generally, against corresponding disease symptoms,after raw material ingredients required for the liquid formulationcomposition are determined, the adding amount of each raw materialingredient is continuously changed to enable the finally obtained liquidformulation composition to meet the conditions of the invention, and atthis time, the adding amount of each raw material ingredient can berecorded. When the liquid formulation composition with the samecomposition is prepared subsequently, just based on the known addingamount of each raw material ingredient, the formulation can be directlyprepared.

Preferably, in the liquid formulation composition, the content of thesurfactant is in the range from about 0.1 wt % to about 25.0 wt %, andthe content of the solvent is in the range from about 75.0 wt % to about99.9 wt %. When the above surfactant adopts a variety of substances formatching and use, there is no limitation of the relative content of thevarious substances as long as the surface tension and the zeta potentialof the whole liquid formulation composition meet the conditionsdescribed above.

In the invention, in order to better ensure the stability of the liquidformulation composition, prevent the occurrence of sedimentation andprolong the storage time, preferably, the liquid formulation compositiondisclosed herein further includes a stabilizer. The applied stabilizerincludes, but not limited to well-known edible stabilizers by thoseskilled in the art, one of lecithin, poloxamer, saponin, tannin,glycerin fatty acid ester, sucrose fatty acid ester, propanediol fattyacid ester, cholesterol, cholesterol ester, polyethylene glycol,cellulose or its derivatives, dextrin, Arabic gum, tragacanth gum,pectin cellulose cheese, gelatin, alginic acid, or a combinationthereof.

In the stabilizers that can be adopted, some substances, such aslecithin, poloxamer, cholesterol and cholesterol ester, are the same asthe substances adopted by the surfactant. Each substance has betterstability in the liquid formulation composition and can besimultaneously taken as the surfactant and the stabilizer by itself.

The amount of stabilizer in the liquid formulation composition can varywithin a relatively large range, as long as the surface tension of theliquid formulation composition is ensured to be within the rangedescribed herein. Preferably, the content of the stabilizer is in therange from about 0.01 wt % to about 5.0 wt %.

To improve patient compliance, the liquid formulation composition canfurther include one or more flavoring agents, such as, but not limitedto, one of menthol, borneol, lemon oil, patchouli oil, cinnamon oil,jujube tincture, vanillin, peppermint oil, rose oil, eucalyptus oil,spearmint oil, eugenol, citral, jasmine extract, chrysanthemum extract,osmanthus extract, benzyl alcohol, phenylethanol, terpineol, methylcyclopentenolone, α-amyl cinnamic aldehyde, butyric acid, hexanoic acid,isoamyl acetate, benzyl acetate, linalyl acetate, ethyl propionate,ethyl butyrate, isoamyl butyrate, benzyl butyrate, isoamyl isovalerate,ethyl hexanoate, ethyl heptanoate, ethyl lactate, allyl hexanoate,γ-nonalactone, ethyl maltol, allyl cyclohexyl propionate, maltol,γ-undecalactone (peach aldehyde), raspberry ketone (raspberry ketone),benzyl propionate, butyl butyrate, ethyl isovalerate, ethyl formate,benzyl benzoate, methyl pyrazine, 2,3-dimethyl pyrazine, trimethylpyrazine, 2-acetyl pyrazine, 4-methyl-5-(β-hydroxyethyl) thiazole,2-acetyl thiazole, 2,3,5,6-tetramethyl pyrazine, hexadecanal (strawberryaldehyde and bayberry aldehyde), ethyl vanillin, hydroxyl citronellal,as well as well-known flavoring agents and essences in the art, or acombination thereof.

The amount of flavoring agent in the liquid formulation composition canvary within a relatively large range, as long as the surface tension ofthe liquid formulation composition is ensured to be within the rangedescribed herein. Preferably, the content of the flavoring agent is inthe range from about 0.01 wt % to about 5.0 wt %.

To prolong the storage time of the liquid formulation composition andavoid bacteria growth, the liquid formulation composition can furtherinclude a bacteriostatic agent, such as, but not limited to, one ofparabens or its salts, benzoic acid or its salts, benzyl alcohol,phenylethanol, phenylacetic acid, phenoxyethanol, lauric acidmonoglyceride, chlorobutanol, sorbic acid or its salts, calciumpropionate, sodium propionate, dehydroacetic acid or its salts, sodiumdiacetate, glycerol monolaurate, benzalkonium chloride, benzalkoniumbromide, cetrimide, chlorhexidine acetate, propanediol, carbon dioxide,nisin, natamycin, momordicin, thimerosal, mercuric nitrate, or acombination thereof.

The amount of bacteriostatic agent in the liquid formulation compositioncan vary within a relatively large range, as long as the bacteria growthof the liquid formulation composition is ensured to be within theacceptable range. Preferably, the content of the bacteriostatic agent isin the range from about 0.001 wt % to about 2.0 wt %.

The liquid formulation composition of the invention can also include anantioxidant. The antioxidant is selected from, but not limited to, oneof tert-butyl hydroxy anisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, ascorbyl palmitate, dilaurylthiodipropionate, 4-hexyl resorcinol, tocopherol (vitamin E), L-ascorbicacid, D-sodium erythorbate, tea polyphenols, rosemary extract, gingerextract, sugar alcohols, amino acids or dipeptide type amino acids, or acombination thereof.

The amount of antioxidant in the liquid formulation composition can varywithin a relatively large range, as long as the surface tension of theliquid formulation composition is ensured to be within the rangedescribed herein. Preferably, the content of the antioxidant is in therange from about 0.001 wt % to about 5.0 wt %.

In the invention, when the liquid formulation composition includes thebacteriostatic agent, the flavoring agent, the stabilizer and theantioxidant, the content of each ingredient in the liquid formulationcomposition can vary within a relatively large range, for example, asfor the liquid formulation composition, the content of the surfactantcan be in the range from about 0.1 wt % to about 25.0 wt %, the contentof the solvent can be in the range from about 58.0 wt % to about 99.878wt %, the content of the bacteriostatic agent can be in the range fromabout 0.001 wt % to about 2.0 wt %, the content of the flavoring agentcan be in the range from about 0.01 wt % to about 5.0 wt %, the contentof the stabilizer can be in the range from about 0.01 wt % to about 5.0wt %, and the content of the antioxidant can be in the range from about0.001 wt % to about 5.0 wt %.

To improve the comprehensive treatment effects of the liquid formulationcomposition of the invention, preferably, the liquid formulationcomposition can also include one or more active pharmaceuticalingredients. Active pharmaceutical ingredients include one of medicinesfor treating rhinitis, sinusitis, lower respiratory tract inflammation,otitis media, otitis externa, xerostomia, xerophthalmia andxeromycteria, or a combination thereof.

Active pharmaceutical ingredients for treating rhinitis, sinusitis andlower respiratory tract inflammation, such as the active pharmaceuticalingredient for treating rhinitis and lower respiratory tractinflammation includes, but not limited to, one of cortisone,hydrocortisone, beclomethasone, triamcinolone acetonide, mometasone,dexamethasone, fluocinolone acetonide, budesonide, fluticasone and otherglucocorticoids; ephedrine hydrochloride, xylometazoline hydrochlorideand other vasoconstrictors; levocabastine hydrochloride, azelastinehydrochloride and other antihistamines; or fructus xanthii, dandelion,radix scutellariae, bitter gourd, herba ephedrae, flos magnoliae, herbaasari, radix angelicae dahuricae, rhizome acori tatarinowii, catechu,Longjing tea, cortex phellodendroni, other traditional Chinese medicinesor its extracts, or a combination thereof.

The amount of the active pharmaceutical ingredient employed in theliquid formulation composition of the invention for treating rhinitis,sinusitis and lower respiratory tract inflammation is selected such thatit is both effective and safe for administration to a subject.

The liquid formulation composition of the invention can further includeone or more active pharmaceutical ingredients for treating otitisexterna, otitis media and lower respiratory tract inflammation, forexample, the active pharmaceutical ingredient for treating otitisexterna, otitis media and lower respiratory tract inflammation includes,but not limited to, one of ofloxacin, levofloxacin, norfloxacin,lomefloxacin, tosufloxacin, sparfloxacin, roxithromycin, chloromycetin,penicillin, clindamycin, nitrofurazone, amoxicillin, ampicillin,clavulanate potassium, cefaclor, cefixime, cefdinir, cephradine,cephalexin, cefpodoxime, cefuroxime axetil, cefprozil, azithromycin,minocycline, acetyl midecamycin, acetylspiramycin or other antibiotics;metronidazole or other antivirals; cortisone, triamcinolone acetonide orother glucocorticoids; and musk, potassium aluminium sulfate anhydrous,calamine, borneol, cochineal, cacumen platycladi, echinacea root,baptisia tinctoria root, other traditional Chinese medicines or itsextracts, or a combination thereof.

The amount of the active pharmaceutical ingredient employed in theliquid formulation composition of the invention for treating otitisexterna, otitis media and lower respiratory tract inflammation isselected such that it is both effective and safe for administration to asubject.

The liquid formulation composition of the invention can also include oneor more ingredients for treating otitis externa, lower respiratory tractinflammation, xeromycteria, xerostomia and xerophthalmia, including butnot limited to one of D-panthenol, glycerin, hyaluronic acid,butanediol, polyethylene glycol, propanediol, hexanediol, xylitol,sorbitol, or a combination thereof.

The amount of the active pharmaceutical ingredient employed in theliquid formulation composition of the invention for treating otitisexterna, lower respiratory tract inflammation, xeromycteria, xerostomiaand xerophthalmia is selected such that it is both effective and safefor administration to a subject.

Exemplarily, in the liquid formulation composition, the content of theactive pharmaceutical ingredient can be in the range from about 0.001 wt% to about 5.0 wt %. As described above, in the liquid formulationcomposition, the content of the surfactant is in the range from about0.1 wt % to about 25.0 wt %, the content of the solvent is in the rangefrom about 70.0 wt % to about 99.899 wt %, and the content of the activepharmaceutical ingredient is in the range from about 0.001 wt % to about5.0 wt %. When the liquid formulation composition further contains oneof bacteriostatic agent, flavoring agent, stabilizer, antioxidant, or acombination thereof, for the whole liquid formulation composition, thecontent of the surfactant can be in the range from about 0.1 wt % toabout 25.0 wt %, the content of the solvent can be in the range of 53.0wt % to about 99.877 wt %, the content of the bacteriostatic agent canbe in the range from about 0.001 wt % to about 2.0 wt %, the content ofthe flavoring agent can be in the range from about 0.01 wt % to about5.0 wt %, the content of the stabilizer can be in the range of 0.01 wt %to about 5.0 wt %, the content of the antioxidant can be in the rangefrom about 0.001 wt % to about 5.0 wt %, and the content of the activepharmaceutical ingredient can be in the range from about 0.001 wt % toabout 5.0 wt %.

According to the invention, preferably, the containment vessel is ananti-contamination sprayer or an anti-contamination dropping device.

In certain embodiments of the invention, the containment vessel forholding the liquid formulation composition is an anti-contamination drugdelivery device, such as an anti-contamination sprayer or ananti-contamination dropping device. There are anti-contamination drugdelivery devices known in the prior art, such as the Ophthalmic SqueezeDispenser (OSD) of Aptar Company. The anti-contamination medicinedelivery device is based on a pure mechanical principle; and through adrip nozzle sealing technology and an air filtration technology,microbes can be effectively prevented from polluting the liquidformulation composition, and the balance of pressure inside and outsidethe whole package can be kept. Addition of the bacteriostatic agent isnot required, so that the irritation problem caused by thebacteriostatic agent can be greatly reduced; and meanwhile, when thedevice is adopted, filling can be still performed by using the existingmethod.

As the anti-contamination medicine delivery device is used for holdingthe liquid formulation composition, the long-term sterility of theliquid formulation composition can be ensured under the situation wherea bacteriostatic agent is not added.

In certain embodiments, if the anti-contamination sprayer or theanti-contamination dropping device is used and when the liquidformulation composition includes the flavoring agent, the stabilizer andthe antioxidant, the content of each ingredient in the liquidformulation composition can vary within a relatively large range, forexample, as for the whole liquid formulation composition, the content ofthe surfactant can be in the range from about 0.1 wt % to about 25.0 wt%, the content of the solvent can be in the range of 60.0 wt % to about99.879 wt %, the content of the flavoring agent can be in the range fromabout 0.01 wt % to about 5.0 wt %, the content of the stabilizer can bein the range from about 0.01 wt % to about 5.0 wt %, and the content ofthe antioxidant can be in the range from about 0.001 wt % to about 5.0wt %.

Under the above situation, if the liquid formulation composition furtherincludes the above-mentioned active pharmaceutical ingredient, at thistime, in the liquid formulation composition in the anti-contaminationsprayer or the anti-contamination dropping device, the content of thesurfactant is in the range from about 0.1 wt % to about 25.0 wt %, thecontent of the solvent is in the range from about 55.0 wt % to about99.878 wt %, the content of the flavoring agent is in the range fromabout 0.01 wt % about 5.0 wt %, the content of the stabilizer is in therange from about 0.01 wt % to about 5.0 wt %, the content of theantioxidant is in the range from about 0.001 wt % to about 5.0 wt %, andthe content of the active pharmaceutical ingredient is in the range fromabout 0.001 wt % to about 5.0 wt %.

According to certain embodiments of the invention, the containmentvessel for containing the liquid formulation composition can adopt thevarious common sprayers or dropping devices in the field ofpharmaceuticals. There are no special requirements on the structures ofthe sprayer and the dropping device in the invention, and the sprayerand the dropping device are commercially available.

Meanwhile, in certain embodiments, the invention provides a preparationmethod of the formulation. The method includes:

(S1). Dispersing a liquid surfactant in ultrasound of 40 KHz to about 60KHz for about 1 minute to about 3 minutes;

(S2). Uniformly mixing the liquid surfactant with a solvent under thestirring condition at the rotational speed of more than 3000 rpm to forma liquid formulation composition with liquid particles which contain thesurfactant and are dispersed in the solvent, wherein the surface tensionof the liquid formulation composition is less than 60 mN/m, and theabsolute value of zeta potential is more than 15 mV; and

(S3). Filling the liquid formulation composition into a containmentvessel, wherein the containment vessel is a sprayer or a dropping deviceor an anti-contamination sprayer or an anti-contamination droppingdevice.

In the above preparation method, the surfactant can be selected from oneof lecithin, sterol, pulmonary surfactant, poloxamer, dipalmitoylphosphatidylcholine, cholesterol, cholesteryl ester, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, polyethyleneglycol, or a combination thereof. Various surfactants meeting therequirements as provided herein can be directly obtained commercially.

The solvent is one of water, ethanol, glycerol, medical silicone oil,edible vegetable oil, or a combination thereof. Preferably, water ischosen as solvent and can reduce the irritation to the user.

According to the invention, in step (S1), when the adopted surfactantraw material is liquid at room temperature, the surfactant can bedirectly dispersed in ultrasound of 40 KHz to about 60 KHz for about 1minute to about 3 minutes At this time, the surface tension and the zetapotential of the liquid formulation composition can fall within therange described above by only adjusting the relative content of thesolvent and the surfactant. Preferably, in the liquid formulationcomposition, the content of the surfactant is in the range from about0.1 wt % to about 25.0 wt %, and the content of the solvent is in therange from about 75.0 wt % to about 99.9 wt %.

When the adopted surfactant is solid at room temperature, the solidsurfactant raw material needs to be first processed into the liquidstate. Then, the liquid surfactant is dispersed in ultrasound of 40 KHzto about 60 KHz for about 1 minute to about 3 minutes

The method for processing the solid surfactant raw material into theliquid state can adopt the method known to the skilled in the art, forexample, the solid surfactant raw material can be mixed with a substancewhich can dissolve the solid surfactant raw material to dissolve. It canbe understood that for the different solid active substances, thesubstances that can dissolve the solid surfactant raw materials may bedifferent. In the invention, the substances that dissolve the solidsurfactant raw materials can be any substances known to those of skillin the art, as long as the solid surfactant raw material can bedissolved.

According to the invention, in step (S2), preferably, the surfactant andthe solvent are uniformly mixed under the stirring condition at therotational speed of more than 3000 rpm. At this time, the liquidparticles including the surfactant, which have the volume averageparticle size of less than about 100 μm, can be formed in the solvent.For example, the liquid particles with the volume average particle sizein the range from about 1 μm to about 100 μm can be formed. The liquidparticles can stably exist in the solvent, and the the liquidformulation composition exists as an emulsion. As the liquid particleswith the volume average particle size in the range from about 1 μm toabout 100 μm are formed in the solvent, the required rotational speed isdifferent for the different liquid surfactants and can be adjusted bythose of skill in the art according to actual situations with thebenefit of the instant disclosure. As known to those skilled in the art,along with the improvement of the stirring rotational speed and theprolongation of the time, the liquid particles with the smaller volumeaverage particle size can be formed.

Specifically, the solvent and the surfactant are mixed, for example, thesurfactant is added into the solvent. After mixing, the surface tensionand the zeta potential of the solvent/surfactant mixture are detected,when the surface tension is less than 60 mN/m (or a preset targetsurface tension value) and the absolute value of zeta potential is morethan 15 mV, the formulation is obtained, and the liquid formulationcomposition disclosed herein can be obtained. The surface tension of theliquid formulation composition can be obtained by testing with anautomatic surface tension tester (US Kino, A601). The zeta potential ofthe liquid formulation composition can be obtained by testing with azeta potential tester NANOTRAC WAVE (MicroTrac, US). In the preparationmethod, the specific surfactant and the solvent were adopted and therelative content thereof are as described above, for example, in theliquid formulation composition, the content of the surfactant is in therange from about 0.1 wt % to about 25.0 wt %, and the content of thesolvent is in the range from about 75.0 wt % to about 99.9 wt %.

Preferably, after step (S2), the preparation method further includes thesteps of ultrasonic crushing or high-pressure homogenization. Throughultrasonic crushing or high-pressure homogenization, the liquidparticles can be further homogenized to get smaller liquid particles andform the liquid particles with the volume average particle size in therange from about 50 nm to about 500 nm. Wherein, the liquid particlescan be dispersed in the solvent more stably. The volume average particlesize of the liquid particles can be directly tested with variousexisting particle size detection devices (such as laser particle sizeanalyzer Mastersizer 2000 (Malvern Instruments Ltd., UK)).

It can be understood that the liquid particles in the liquid formulationcomposition can be formed by the surfactant, or by the surfactant andother substances in the liquid formulation composition. The volumeaverage particle size tested with the detection device is the volumeaverage particle size of the liquid particles, including the liquidparticles formed by the surfactant or by the surfactant and othersubstances in the liquid formulation composition.

In certain embodiments of the invention, the stability of the liquidformulation composition can be further improved by adjusting the pH ofthe liquid formulation composition to the range from about 6.0 to about7.4. It can be understood that, when the liquid formulation compositionis prepared, the pH of initial mixtures including all raw materialingredients, which are obtained by adopting different raw materials, canbe different; and if the pH of the initial mixture is within the aboverange, the pH does not need to be adjusted any more. If the pH is notwithin the above range, preferably, the pH of the liquid formulationcomposition can be adjusted through the existing method. For example,the adjustment can be performed through the way of adding a buffersolution. A buffer solution can be selected from a citric acid-sodiumcitrate buffer solution, an acetic acid-sodium acetate buffer solution,a phosphoric acid buffer solution, an HEPES or Tris-citric acid buffersolution. Preferably, the buffer system is the HEPES and Tris-citricacid buffer solution with the pH in the range from about 6.0 to about7.4.

The amount of each buffer solution added is selected to allow the pH ofthe liquid formulation composition to reach the desired level.

According to certain embodiments of the invention, when the liquidformulation composition is prepared, one or more of bacteriostaticagent, flavoring agent, stabilizer, antioxidant can be added accordingto actual using demands. Examples of bacteriostatic agent, the flavoringagent, the stabilizer and the antioxidant are as described herein.

The amount of each of bacteriostatic agent, flavoring agent, stabilizerand antioxidant is selected as described herein, for example, the addingamount of the surfactant is in the range from about 0.1 wt % to about25.0 wt %, the adding amount of the solvent is in the range of58.0-99.878 wt %, the adding amount of the bacteriostatic agent is inthe range from about 0.001 wt % to about 2.0 wt %, the adding amount ofthe flavoring agent is in the range from about 0.01 wt % to about 5.0 wt%, the adding amount of the stabilizer is in the range from about 0.01wt % to about 5.0 wt %, and the adding amount of the antioxidant is inthe range from about 0.001 wt % to about 5.0 wt %.

If the anti-contamination sprayer or the anti-contamination droppingdevice is used for the preparation of liquid formulation composition,only one of flavoring agent, stabilizer, antioxidant, or a combinationthereof can be added, and the bacteriostatic agent does not need to beadded. Specifically, the adding amount of each of flavoring agent,stabilizer and antioxidant is also as described herein, for example, theadding amount of the surfactant is in the range from about 0.1 wt % toabout 25.0 wt %, the adding amount of the solvent is in the range fromabout 60.0 wt % to about 99.879 wt %, the adding amount of the flavoringagent is in the range from about 0.01 wt % to about 5.0 wt %, the addingamount of the stabilizer is in the range from about 0.01 wt % to about5.0 wt %, and the adding amount of the antioxidant is in the range fromabout 0.001 wt % to about 5.0 wt %.

According to certain embodiments of the invention, when the liquidformulation composition is prepared, one or more active pharmaceuticalingredients can also be added. The active pharmaceutical ingredientsinclude, but not limits to, one of active pharmaceutical ingredient fortreating rhinitis, sinusitis, lower respiratory tract inflammation,otitis media, otitis externa, xerostomia, xerophthalmia, xeromycteria,or a combination thereof to enable the liquid formulation composition tohave better comprehensive treatment effects. Exemplary activepharmaceutical ingredients are as described herein.

Specifically, there are no particular limitations regarding the step ofadding the active pharmaceutical ingredient, for example, the activepharmaceutical ingredient can be mixed with the surfactant and the liketogether for preparation.

The amount of active pharmaceutical ingredient used is selected so thatthe liquid formulation composition effective and safe. In specificpreparation, the amount of active pharmaceutical ingredient can beadjusted according particular situations by those skilled in the art.Examples amounts of active pharmaceutical ingredient are describedherein.

The various active pharmaceutical ingredients added for improving thecomprehensive performances of the liquid formulation composition canexist in various forms, including the form of liquid particles. As theadding amount of the various substances are trace amount compared tothose of the surfactant and the solvent, the added various substanceshave little influence on the volume average particle size of the liquidparticles in the liquid formulation composition and can be neglected inthe invention.

In manufacturing, for example, after the liquid formulation compositionis prepared, it is filled into a nasal sprayer or a dropping device(those skilled in the art can select whether to adopt ananti-contamination sprayer or an anti-contamination dropping device asneed), and then the nasal sprayer or the dropping device is sealed.After testing for appearance, volume, content of main ingredient, weightper spray (or weight per drop), sedimentation rate, microbial limit andother quality parameters, outside packaging is performed to obtain thefinal product.

The existing common packages, including containment vessels, pumps (orvalves) and triggers, can be adopted for packaging.

The liquid formulation composition of the invention can be filled intothe sprayer so as to be used in a form of spray.

The liquid formulation composition of the invention can also be used asnasal drops or ear drops. For the nasal drops or ear drops, the commonpackages include containment vessels and droppers.

The filling method of the liquid formulation composition is well knownby those skilled in the art.

According to the invention, when the anti-contamination sprayer or theanti-contamination dropping device is adopted as the containment vessel,the preparation process of the liquid formulation composition is notaffected. When the liquid formulation composition is filled into theanti-contamination sprayer or the anti-contamination dropping device,the filling method is also well known by those skilled in the art.

It is understood that, in the invention, the bacteriostatic agent doesnot need to be added in the liquid formulation composition when theanti-contamination sprayer or the anti-contamination dropping device isadopted. The content and effects of other components in the liquidformulation composition are not affected by the anti-contaminationsprayer or the anti-contamination dropping device.

An objective of the invention is to provide a liquid formulationcomposition that is stable and can be used in a form of spray or drop,and a preparation method thereof. The formulation can be used intreatment of otitis media, otitis externa, rhinitis, sinusitis,xeromycteria, xerostomia and xerophthalmia.

Without wishing to be bound by the theory, it is believed that theaction mechanism of the liquid formulation composition disclosed hereinis that the relatively low surface tension is provided at the locationto relieve the symptoms. In the description of the invention, only themethod of use to otitis media is taken as an example for description.With the benefit of the instant disclosure, those skilled in the art canrecognize that the liquid formulation composition provided herein isalso effective for other disease symptoms (such as otitis externa,rhinitis, sinusitis and the like) caused by excessive secretion of mucusand blocking of a cavity canal, besides otitis media.

The invention is further described through the following non-limitingexamples.

EXAMPLES Example I

The exemplary embodiment describes a formulation and a preparationmethod thereof disclosed herein.

2.38 g of hydrogenated phospholipid, 0.12 g of sterol, 0.4 g of methylparaben, 0.2 g of ethyl paraben and 0.1 g of menthol were weighed andplaced in a beaker. 1 mL of anhydrous ethanol was added and dissolvedwith ultrasonic (40 KHz). While mixing at a high-speed stirring (6000rpm), water was continuously added till the final volume of 100 mL, andmixed well. The formulation was filled into a containment vessel, suchas sprayer or a dropping device, and the containment vessel was sealed.After the results of appearance, volume, content of main ingredient,weight per spray (or weight per drop), microbial limit and other testswere found to meet the requirements, outside packaging was performed toobtain the final product.

The surface tension of a final product was tested to be 48.851 mN/m byan automatic surface tensionmeter (US Kino, A601). The particle sizedistribution of the product was determined by Mastersizer 2000 (MalvernInstruments Ltd., UK), and the volume average particle size was 2.342μm. The zeta potential of the product was determined by NANOTRAC WAVE(MicroTrac, US), and the result was −28.5 mV. The pH of the product wasdetermined by a pH meter (Shanghai Leici, PHSJ3F), and the result was6.2.

After the formulation was centrifuged at 3750 rpm for 5 hours, there wasno observable precipitate at the bottom.

Example II

The exemplary embodiment describes a formulation and a preparationmethod thereof disclosed herein.

2.35 g of soya lecithin, 0.15 g of poloxamer, 0.08 g of vitamin E and0.5 g of phenylethanol were weighed and placed in a beaker. 1 mL ofanhydrous ethanol was added and dissolved with ultrasonic (40 KHz).While mixing at high speed (6000 rpm), water was continuously added tillthe final volume of 100 mL, and mixed well. The formulation was filledinto a containment vessel, such as sprayer or a dropping device and thecontainment vessel was sealed. After the results of appearance, volume,content of main ingredient, weight per spray (or weight per drop),microbial limit and other tests were found to meet the requirements,outside packaging was performed for preparation to obtain the finalproduct.

The surface tension of a final product was tested to be 16.252 mN/m byan automatic surface tensionmeter (US Kino, A601). The particle sizedistribution of the product was determined by Mastersizer 2000 (MalvernInstruments Ltd., UK), and the volume average particle size was 5.712μm. The zeta potential of the product was determined by NANOTRAC WAVE(MicroTrac, US), and the result was −25.8 mV. The pH of the product wasdetermined by a pH meter (Shanghai Leici, PHSJ3F), and the result was6.1.

After the mixed solution was centrifuged at 3750 rpm for 5 hours, therewas no observable precipitate at the bottom.

Example III

The exemplary embodiment describes a formulation and a preparationmethod thereof disclosed herein.

3.75 g of soya lecithin and 0.64 g of vitamin E were weighed and placedin a beaker. 1 mL of anhydrous ethanol was added and dissolved withultrasonic (40 KHz). The ethanol solution was added into 0.05 g oflauric acid monoglyceride and 99 mL of Tris-citric acid buffer solutionwith the pH in the range of 6.0-7.4 while a high-speed stirring (6000rpm). The ultrasonic homogenization was further performed in anultrasonic homogenizer. Then, the formulation was filled intocontainment vessel, such as an anti-contamination medicine deliverydevice (OSD) and sealed. After the results of appearance, volume,content of main ingredient, weight per spray (or weight per drop),microbial limit and other tests were found to meet the requirements,outside packaging was performed to obtain the final product.

The surface tension of a final product was tested to be 26.225 mN/m byan automatic surface tensionmeter (US Kino, A601). The particle sizedistribution was determined by Mastersizer 2000 (Malvern InstrumentsLtd., UK), and the volume average particle size was 223 nm. The zetapotential of the product was determined by NANOTRAC WAVE (MicroTrac,US), and the result was −32.2 mV. The pH of the product was determinedby a pH meter (Shanghai Leici, PHSJ3F), and the result was 6.5.

After centrifugation at 3750 rpm for 5 hours, there was no observableprecipitate at the bottom.

Example IV

The exemplary embodiment describes a formulation and a preparationmethod thereof disclosed herein.

3.75 g of soya lecithin, 0.013 g of vitamin E and 0.1 g of menthol wereweighed and placed in a beaker. 1 mL of anhydrous ethanol was added anddissolved with ultrasonic (40 KHz). The ethanol solution was added into99 mL of water while a high-speed stirring (6000 rpm) and mixed well.Homogenization was performed by a high-pressure homogenizer for 10minutes. Then, the formulation was filling into containment vessel, suchas an anti-contamination medicine delivery device (OSD) and thecontainment vessel was sealed. After the results of appearance, volume,content of main ingredient, weight per spray (or weight per drop),microbial limit and other tests were found to meet the requirements,outside packaging was performed to obtain the final product.

The surface tension of a final product was tested to be 28.253 mN/m byan automatic surface tensionmeter (US Kino, A601). The particle sizedistribution was determined by Mastersizer 2000 (Malvern InstrumentsLtd., UK), and the volume average particle size was 252 nm. The zetapotential of the product was determined by NANOTRAC WAVE (MicroTrac,US), and the result was −21.2 mV. The pH value of the product wasdetermined by a pH meter (Shanghai Leici, PHSJ3F), and the result was6.0.

After centrifugation at 3750 rpm for 5 hours, there was no observableprecipitate at the bottom.

Example V

The exemplary embodiment describes a formulation and a preparationmethod thereof disclosed herein.

2.5 g of soya lecithin, 0.01 g of vitamin E, 0.4 g of methyl paraben,0.2 g of ethyl paraben, 0.5 g of phenylethanol and 0.1 g of menthol wereweighed and placed in a beaker. 1 mL of anhydrous ethanol was added anddissolved with ultrasonic (40 KHz). While mixing at high-speed (6000rpm), 0.12 g of poloxamer was dissolved in 5 mL of water, the watersolution containing the poloxamer was mixed with the ethanol solutionunder high-speed stirring. Water was continuously added till the finalvolume of 100 mL, and then mixed well. The formulation was filled into acontainment vessel, such as sprayer or a dropping device and thecontainment vessel was sealed. After the results of appearance, volume,content of main ingredient, weight per spray (or weight per drop),microbial limit and other tests were found to meet the requirements,outside packaging was performed to obtain the final product.

The surface tension of a final product was tested to be 20.185 mN/m byan automatic surface tensionmeter (US Kino, A601). The particle sizedistribution of the product was determined by Mastersizer 2000 (MalvernInstruments Ltd., UK), and the volume average particle size was 4.422μm. The zeta potential of the product was determined by NANOTRAC WAVE(MicroTrac, US), and the result was −19.8 mV. The pH of the product wasdetermined by a pH meter (Shanghai Leici, PHSJ3F), and the result was6.1.

After the mixed solution is centrifuged at 3750 rpm for 5 hours, therewas no observable precipitate at the bottom.

Example VI

The exemplary embodiment describes a formulation and a preparationmethod thereof disclosed herein.

3.75 g of soya lecithin, 0.64 g of vitamin E and 0.5 g of phenylethanolwere weighed and placed in a beaker. 1 mL of anhydrous ethanol was addedand dissolved with ultrasonic (40 KHz). The ethanol solution was addedinto 99 mL of water containing 0.15 g of poloxamer while a high-speedstirring (6000 rpm), and ultrasonic homogenization was further performedin an ultrasonic homogenizer. Then, the formulation was filled intocontainment vessel, such as a sprayer or a dropping device and thecontainment vessel was sealed. After the results of appearance, volume,content of main ingredient, weight per spray (or weight per drop),microbial limit and other tests were found to meet the requirements,outside packaging was performed to obtain the final product.

The surface tension of a final product was tested to be 16.425 mN/m byan automatic surface tensionmeter (US Kino, A601). The particle sizedistribution was determined by Mastersizer 2000 (Malvern InstrumentsLtd., UK), and the volume average particle size was 275 nm. The zetapotential of the product was determined by NANOTRAC WAVE (MicroTrac,US), and the result was −17.8 mV. The pH of the product was determinedby a pH meter (Shanghai Leici, PHSJ3F), and the result was 5.9.

After the mixed solution was centrifuged at 3750 rpm for 5 hours, therewas no observable precipitate at the bottom.

Example VII

The exemplary embodiment describes a formulation and a preparationmethod thereof disclosed herein.

1.38 g of hydrogenated phospholipid, 1.0 g of soya lecithin, 0.12 g ofsterol, 0.4 g of methyl paraben, 0.2 g of ethyl paraben and 0.1 g ofmenthol were weighed and placed in a beaker. 1 mL of anhydrous ethanolwas added and dissolved with ultrasonic (40 KHz). While mixing athigh-speed (6000 rpm), water was continuously added till the finalvolume of 100 mL and mixed well. The formulation was homogenized for 10minutes by a high-pressure homogenizer and filled into containmentvessel, such as a sprayer or a dropping device, the containment vesselwas sealed. After the results of appearance, volume, content of mainingredient, weight per spray (or weight per drop), microbial limit andother tests were found to meet the requirements, outside packaging wasperformed to obtain the final product.

The surface tension of a final product was tested to be 28.518 mN/m byan automatic surface tensionmeter (US Kino, A601). The particle sizedistribution of the product was determined by Mastersizer 2000 (MalvernInstruments Ltd., UK), and the volume average particle size was 356 nm.The zeta potential of the product was determined by NANOTRAC WAVE(MicroTrac, US), and the result was −35.8 mV. The pH of the product wasdetermined by a pH meter (Shanghai Leici, PHSJ3F), and the result was6.2.

After the mixed solution was centrifuged at 3750 rpm for 5 hours, therewas no observable precipitate at the bottom.

Example VIII

The exemplary embodiment describes a formulation (containing a activepharmaceutical ingredient for treating rhinitis and sinusitis) and apreparation method thereof disclosed herein.

1.0 g of soya lecithin, 0.12 g of sterol, 4 mg of triamcinoloneacetonide, 0.4 g of methyl paraben, 0.2 g of ethyl paraben and 0.1 g ofmenthol were weighed and placed in a beaker. 1 mL of anhydrous ethanolwas added and dissolved with ultrasonic (40 KHz). While mixing athigh-speed stirring (6000 rpm), water was continuously added till thefinal volume of 100 mL and mixed well. The formulation was homogenizedfor 10 minutes by a high-pressure homogenizer and filled intocontainment vessel, such as a sprayer or a dropping device. Thecontainment vessel was sealed. After the results of appearance, volume,content of main ingredient, weight per spray (or weight per drop),microbial limit and other tests were found to meet the requirements,outside packaging was performed for preparation to obtain the finalproduct.

The surface tension of a final product was tested to be 24.518 mN/m byan automatic surface tensionmeter (US Kino, A601). The particle sizedistribution of the product was determined by Mastersizer 2000 (MalvernInstruments Ltd., UK), and the volume average particle size was 305 nm.The zeta potential of the product was determined by NANOTRAC WAVE(MicroTrac, US), and the result was −25.8 mV. The pH of the product wasdetermined by a pH meter (Shanghai Leici, PHSJ3F), and the result was5.7.

After the mixed solution was centrifuged at 3750 rpm for 5 hours, therewas no observable precipitate at the bottom.

Example IX

The exemplary embodiment describes a formulation (containing a activepharmaceutical ingredient for treating otitis media) and a preparationmethod thereof disclosed herein.

1.0 g of soya lecithin, 0.12 g of sterol, 0.4 g of methyl paraben, 0.2 gof ethyl paraben and 0.1 g of menthol were weighed and placed in abeaker. 1 mL of anhydrous ethanol was added and dissolved withultrasonic (40 KHz). While mixing at high-speed (6000 rpm), a watersolution containing 0.3 wt % of levofloxacin hydrochloride (calculatedby levofloxacin) was continuously added till the final volume of 100 mLand mixed well. The formulation was homogenized for 10 minutes by ahigh-pressure homogenizer, and filled into containment vessel, such as asprayer or a dropping device. The containment vessel was sealed. Afterthe results of appearance characters, volume, content of mainingredient, weight per spray (or weight per drop), microbial limit andother tests were found to meet the requirements, outside packaging wasperformed to obtain the final product.

The surface tension of a final product was tested to be 27.184 mN/m byan automatic surface tensionmeter (US Kino, A601). The particle sizedistribution of the product was determined by Mastersizer 2000 (MalvernInstruments Ltd., UK), and the volume average particle size was 235 nm.The zeta potential of the product was determined by NANOTRAC WAVE(MicroTrac, US), and the result was −43.9 mV. The pH value of theproduct was determined by pH meter (Shanghai Leici, PHSJ3F), and theresult was 5.8.

After the mixed solution was centrifuged at 3750 rpm for 5 hours, therewas no observable precipitate at the bottom.

Example X

The exemplary embodiment is used for describing a formulation and apreparation method thereof disclosed herein.

0.1 g of Poloxamer 188, 0.8 mg of phenylethanol were weighed and placedin a beaker. Water was added to make up 100 mL to dissolve and mix well.The solution was filled into containment vessel, such as a sprayer or adropping device. The containment vessel was sealed. After the results ofappearance characters, volume, content of main ingredient, weight perspray (or weight per drop), microbial limit and other tests were foundto meet the requirements, outside packaging was performed to obtain thefinal product.

The surface tension of a final product was tested to be 25.851 mN/m byan automatic surface tensionmeter (US Kino, A601). The pH value of theproduct was determined by pH meter (Shanghai Leici, PHSJ3F), and theresult was 5.7.

Example XI

The exemplary embodiment is used for describing a formulation(containing a active pharmaceutical ingredient for treating rhinitis andsinusitis) and a preparation method thereof disclosed herein.

0.1 g of Poloxamer 188, 0.8 mg of phenylethanol, and 60 mg ofdexamethasone sodium phosphate (calculated as dexamethasone) wereweighed and placed in a beaker. 10 mL of water was added to dissolvecompletely. Trs-citric acid buffer at pH 6.5 was added int to theobtained mixture solution till final volume to 100 mL, mixed well andfilled into containment vessel, such as a sprayer or a dropping device.The containment vessel was sealed. After the results of appearancecharacters, volume, content of main ingredient, weight per spray (orweight per drop), microbial limit and other tests were found to meet therequirements, outside packaging was performed to obtain the finalproduct.

The surface tension of a final product was tested to be 25.512 mN/m byan automatic surface tensionmeter (US Kino, A601). The pH value of theproduct was determined by pH meter (Shanghai Leici, PHSJ3F), and theresult was 6.5.

Example XII

The exemplary embodiment describes a formulation (containing a activepharmaceutical ingredient for treating otitis media) and a preparationmethod thereof disclosed herein.

0.1 g of Poloxamer 188, 0.3 g of levofloxacin hydrochloride (calculatedas levofloxacin) were weighed and placed in a beaker. 10 mL of water wasadded to dissolve completely. HEPES buffer at pH 6.0 was added in to theobtained mixture solution till final volume to 100 mL and mixed well andfilled into containment vessel, such as a sprayer or a dropping device.The containment vessel was sealed. After the results of appearancecharacters, volume, content of main ingredient, weight per spray (orweight per drop), microbial limit and other tests were found to meet therequirements, outside packaging was performed to obtain the finalproduct.

The surface tension of a final product was tested to be 24.125 mN/m byan automatic surface tensionmeter (US Kino, A601). The pH value of theproduct was determined by pH meter (Shanghai Leici, PHSJ3F), and theresult was 6.0.

Comparative Example I

The exemplary comparative example is used for comparative description ofa liquid formulation composition and a preparation method thereofdisclosed herein.

2.5 g of hydrogenated phospholipid was weighed and placed in acontainment vessel. Water was added till the final volume of 100 mL, anddissolved with ultrasonic (40 KHz), while mixing with a magnetic stirrerfor 30 minutes.

The particle size distribution of the product was determined byMastersizer 2000 (Malvern Instruments Ltd., UK), and the volume averageparticle size was 525.234 μm. The zeta potential of the product wasdetermined by NANOTRAC WAVE (MicroTrac, US), and the result was −2.5 mV.The pH of the product was determined by a pH meter (Shanghai Leici,PHSJ3F), and the result was 5.7.

After the mixed solution was centrifuged at 3750 rpm for 5 hours, therewas significant amount of precipitate at the bottom.

Comparative Example II

The exemplary comparative example is used for comparative description ofa liquid formulation composition and a preparation method thereofdisclosed herein.

5.0 g of soybean phospholipid, 1.0 g of vitamin E and 0.5 g ofphenylethanol were weighed and placed in a containment vessel, 100 mL ofwater was added in a manual stirring state, and mixed.

The particle size distribution was determined by Mastersizer 2000(Malvern Instruments Ltd., UK), and the volume average particle size was785.347 The zeta potential of the product was determined by NANOTRACWAVE (MicroTrac, US), and the result was −2.2 mV. The pH of the productwas determined by a pH meter (Shanghai Leici, PHSJ3F), and the resultwas 5.7.

After the mixed solution was centrifuged at 3750 rpm for 5 hours, therewas significant amount of precipitate at the bottom.

Performance Testing

The exemplary performance testing is performed on the liquid formulationcomposition prepared by the preparation method as follows:

1. Efficacy Test on Animal Model of Otitis Media

The guinea pigs were subjected to general anesthesia by intramuscularinjection of 70 mg/kg of ketamine and subcutaneous injection of 30 mg/Kgof pentobarbital. Followed by injecting inactivated Haemophilusinfluenzae in tympanic cavity to establish the secretory otitis mediaanimal model. Experimental animals were variegated guinea pigs, andrandomly grouped into a normal animal group with 10 animals and 3 modelgroups with 30 successfully modeled animals. The model animals wererandomly grouped into a non-treatment group, a saline treatment groupand a formulation treatment group, 10 animals for each group. The liquidformulation composition prepared in Example II was employed fortreatment by nasal spray. For each guinea pig, the amount of each nasalspray is 2.5 mg, the amount for bilateral nasal cavities was 5 mg andthe liquid formulation composition was sprayed twice every day for 7consecutive days. Tympanograms and auditory brainstem response (ABR)thresholds were recorded, and single-factor analysis of variance wasadopted for statistical analysis.

TABLE 1 Tympanic cavity pressures of groups (da Pa) Group Number Mean SDNormal group 20 33.06 18.75 Non-treatment group 20 140.6 26.00 Salinegroup 20 129.0 21.94 Formulation group 20 28.21 16.78

TABLE 2 LSD Multiple comparisons of tympanic cavity pressures betweengroups Mean Group Comparative group difference P value Formulation groupNon-treatment group 112.4* 0.000 Formulation group Saline group 100.8*0.000 Non-treatment group Normal group 107.6* 0.000 Non-treatment groupSaline group 11.62 0.252 Note: *The difference has statisticalsignificance (P < 0.05)

TABLE 3 ABR thresholds (dB) Group Number Mean SD Normal group 10 14.93.0 Non-treatment group 10 53.0 4.3 Saline group 10 52.6 4.9 Formulationgroup 10 24.6 3.6

TABLE 4 LSD Multiple comparisons of response thresholds between groupsMean Group Comparative group difference P value Formulation groupNon-treatment group 28.4* 0.000 Formulation group Saline group 28.0*0.000 Formulation group Normal group 9.73* 0.000 Non-treatment groupSaline group 0.400 0.513 Note: *The difference has statisticalsignificance (P < 0.05)

The results showed that the ABR threshold of the normal group was(14.9±3.0) dB HL.

The ABR threshold of the non-treatment group increased to (53.0±4.3) dBHL, and had statistical significance in comparison with that of thenormal group.

The ABR threshold of the saline group was (52.6±4.9) dB HL, and had nostatistical significance in comparison with that of the non-treatmentgroup.

After treatment with nasal spray formulation for 7 days, the ABRthreshold of the formulation group reduced to (24.6±3.6) dB HL, and hadstatistical significance in comparison with those of the non-treatmentgroup and the saline group.

Therefore, by the treatment using the liquid formulation composition ofthe invention, the middle ear negative pressures and the ABR thresholdsof the guinea pigs with secretory otitis media were significantlyreduced, and the improvement of these indicators was transformed torapid relief of above-mentioned symptoms of otitis media in clinical.

Based on the similar mechanism, the liquid formulation composition ofthe invention has the same effects for relieving the symptoms of otitisexterna, rhinitis and sinusitis.

2. Testing of Sedimentation Stability

Two final products (0.5 mL/vial) were respectively taken from ExampleII, Example IV and Comparative example II, and centrifuged at 3750 rpmfor 5 hours for sedimentation stability test. By visual observation, asshown in FIG. 1, no observable precipitate was found in each of ExampleII and Example IV, while the obvious precipitates were found inComparative example II.

In the above test, the result of centrifugation at 3750 rpm for 5 hoursequaled to that of normal storage 1 year. As shown in FIG. 1, the liquidformulation composition disclosed herein had desirable stability.

The above exemplary embodiments are only examples and/or preferableembodiments of the invention and are not intended to limit theinvention. Any modifications, equivalent substitutions, improvements andthe like made within the spirit and the mechanism of the inventionshould be protected within the scope of the invention.

In this specification and the appended claims, the singular forms “a,”“an,” and “the” include plural reference, unless the context clearlydictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. Although any methods and materials similar or equivalent tothose described herein can also be used in the practice or testing ofthe present disclosure, the preferred methods and materials are nowdescribed. Methods recited herein may be carried out in any order thatis logically possible, in addition to a particular order disclosed.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made in this disclosure. All such documents arehereby incorporated herein by reference in their entirety for allpurposes. Any material, or portion thereof, that is said to beincorporated by reference herein, but which conflicts with existingdefinitions, statements, or other disclosure material explicitly setforth herein is only incorporated to the extent that no conflict arisesbetween that incorporated material and the present disclosure material.In the event of a conflict, the conflict is to be resolved in favor ofthe present disclosure as the preferred disclosure.

EQUIVALENTS

The representative examples disclosed herein are intended to helpillustrate the invention, and are not intended to, nor should they beconstrued to, limit the scope of the invention. Indeed, variousmodifications of the invention and many further embodiments thereof, inaddition to those shown and described herein, will become apparent tothose skilled in the art from the full contents of this document,including the examples which follow and the references to the scientificand patent literature cited herein. The following examples containimportant additional information, exemplification and guidance that canbe adapted to the practice of this invention in its various embodimentsand equivalents thereof.

What is claimed is: 1-165. (canceled)
 166. A liquid formulationcomposition, comprising water as a solvent; poloxamer; D-panthenol;methyl paraben; and a phospholipid as a surfactant dispersed ordissolved in water, wherein the liquid formulation composition is anemulsion of liquid droplets having volume average particle sizes in therange from about 1 μm to about 100 μm and is characterized by thephospholipid is present in an amount of about 0.0001 wt % to about 25.0wt %, poloxamer is present in an amount of about 0.01 wt % to about 5.0wt %; methyl paraben is present in an amount of about 0.001 wt % toabout 2.0 wt %; a surface tension of less than 30 mN/m, and a pH valuefrom 6.0 to 7.4.
 167. The liquid formulation composition of claim 166,further comprising one of ethanol, glycerol, medical silicone oil andedible vegetable oil, or a combination thereof.
 168. The liquidformulation composition of claim 167, wherein the phospholipid is anatural phospholipid.
 169. The liquid formulation composition of claim168, further comprising xylitol.
 170. The liquid formulation compositionof claim 169, further comprising one of bacteriostatic agent, flavoringagent, stabilizer, antioxidant, or a combination thereof.
 171. Theliquid formulation composition of claim 170, wherein the bacteriostaticagent comprises one of parabens or its salts, benzoic acid or its salts,benzyl alcohol, phenylethanol, phenylacetic acid, phenoxyethanol, lauricacid monoglyceride, chlorobutanol, sorbic acid or its salts, calciumpropionate, sodium propionate, dehydroacetic acid or its salts, sodiumdiacetate, benzalkonium chloride, benzalkonium bromide, cetrimide,chlorhexidine acetate, propanediol, carbon dioxide, nisin, natamycin,momordicin, thimerosal, mercuric nitrate, or a combination thereof; theflavoring agent comprises one of menthol, borneol, lemon oil, patchoulioil, cinnamon oil, jujube tincture, vanillin, peppermint oil, rose oil,eucalyptus oil, spearmint oil, eugenol, citral, jasmine extract,chrysanthemum extract, osmanthus extract, benzyl alcohol, phenylethanol,terpineol, methyl cyclopentenolone, α-amyl cinnamic aldehyde, butyricacid, hexanoic acid, isoamyl acetate, benzyl acetate, linalyl acetate,ethyl propionate, ethyl butyrate, isoamyl butyrate, benzyl butyrate,isoamyl isovalerate, ethyl hexanoate, ethyl heptanoate, ethyl lactate,allyl hexanoate, γ-nonalactone, ethyl maltol, allyl cyclohexylpropionate, maltol, γ-undecalactone, raspberry ketone, benzylpropionate, butyl butyrate, ethyl isovalerate, ethyl formate, benzylbenzoate, methyl pyrazine, 2,3-dimethyl pyrazine, trimethyl pyrazine,2-acetyl pyrazine, 4-methyl-5-(β-hydroxyethyl) thiazole, 2-acetylthiazole, 2,3,5,6-tetramethyl pyrazine, hexadecanal, ethyl vanillin,hydroxyl citronellal, or a combination thereof; the stabilizer comprisesone of lecithin, poloxamer, saponin, tannin, glycerin fatty acid ester,sucrose fatty acid ester, propanediol fatty acid ester, cholesterol,cholesterol ester, polyethylene glycol, cellulose or its derivatives,dextrin, Arabic gum, tragacanth gum, pectin cellulose cheese, gelatin,alginic acid, or a combination thereof; and the antioxidant comprisesone of tert-butyl hydroxy anisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, ascorbyl palmitate, dilaurylthiodipropionate, 4-hexyl resorcinol, tocopherol, L-ascorbic acid,D-sodium erythorbate, tea polyphenols, rosemary extract, ginger extract,sugar alcohols, amino acids, or a combination thereof.
 172. The liquidformulation composition of claim 171, wherein the content of thebacteriostatic agent is in the range from 0.001 wt % to 2.0 wt %, thecontent of the flavoring agent is in the range from 0.01 wt % to 5.0 wt%, and the content of the antioxidant is in the range from 0.001 wt % to5.0 wt %.
 173. The liquid formulation composition of claim 170,comprising borneol, glycerin, butanediol, polyethylene glycol,propanediol, hexanediol or sorbitol, or a combination thereof.
 174. Theliquid formulation composition of claim 170, characterized by anabsolute value of zeta potential of greater than 15 mV for the liquidparticles.
 175. A medicament delivery device, comprising a containmentvessel for holding a liquid comprising an outlet; and held in thecontainment vessel a liquid formulation composition of claim
 166. 176.The medicament delivery device of claim 175, wherein the containmentvessel is configured to function as a sprayer, allowing controlledspraying of the liquid formulation composition out of the outlet. 177.The medicament delivery device of claim 175, wherein the containmentvessel is configured to function as a dropping device, allowingcontrolled dropping of the liquid formulation composition out of theoutlet.